Phenyl-azacykloalkanes

ABSTRACT

Compound of the formula ##STR1## wherein n is 1 or 2, Y is OH, R 1  COO--, R 2  R 3  NCOO-- or R 4  O whereby R 1  is an alkyl group, or a possibly substituted phenyl group, R 2  is an alkyl, phenethyl, or benzyl or phenyl group, R 3  is H or an alkyl group and R 4  is an allyl or benzyl group, and R is an alkyl, hydroxyalkyl, dimethylaminoalkyl or methylthioalkyl group or alkenyl group, processes for their preparations and methods of treatment employing such compounds. The compounds are useful for therapeutic purposes, especially for treatment of disorders in the central nervous system.

TECHNICAL FIELD

This application is a divisional of U.S. application Ser. No. 656,616,filed Oct. 1, 1984, which is a continuation-in-part of U.S. applicationSer. No. 480,089, filed Mar. 30, 1983 (now abandoned), which is acontinuation-in-part of U.S. application Ser. No. 461,504, filed Jan.27, 1983 (now abandoned), which is a continuation of U.S. applicationSer. No. 213,633, filed Dec. 5, 1980 (now U.S. Pat. No. 4,426,386).

The present invention is related to new substitutedphenylazacycloalkanes, and the pure enantiomers, to processes forpreparing such compounds as well as to pharmaceutical preparationsthereof and methods of treatment employing such compounds.

An object of the invention is to provide compounds for therapeutic use,especially having a therapeutic activity in the central nervous system.

BACKGROUND ART

In Chemical Abstracts 69: 867765 (citing Julia, M. et al., Bull. Soc.Chim. Fr. 1968, (3), 1000-7) compounds under the general formula##STR2## are described. Among the compounds mentioned are compoundswherein R^(I) represents m-OCH₃ and R^(II) represents H, CH₃, C₂ H₅, CH₂C₆ H₅, CH₂ CH₂ C₆ H₅ or CH₂ CH₂ C₆ H₄ NO ₂ (p) and wherein R^(I)represents m--OH and R^(II) represents CH₂ CH₂ C₆ H₅ or CH₂ CH₂ C₆ H₄NO₂ (p). Said compounds were prepared for investigation ofpharmacological properties.

Swiss Patent No. 526,536 describes compounds under the formula ##STR3##wherein R^(I) represents H or OH and R^(II) represents H. The compoundsare claimed to have useful pharmacological properties especially asbroncholytic agents.

DE Offenlegungschrift 2 621 536 describes compounds of the formula##STR4## wherein X^(I) is hydrogen or an acyl group and R^(I) is analkyl, alkenyl or phenylalkyl group The compounds are claimed to havedopaminergic properties.

EP-Al-0030526 and Hacksell et al. in J. Med. Chem., vol. 24, p.1475-1482 (1981) describe compounds of the formula ##STR5## wherein n is1 or 2, Y is OH, R¹ COO, R² R³ NCOO--or R⁴ O whereby R¹ is an alkylgroup having 1-5 carbon atoms or a possibly substituted phenyl group, R²is an alkyl group having 1-5 carbon atoms, a phenethyl, benzyl or phenylgroup, R³ is H or an alkyl group having 1-5 carbon atoms, and R⁴ is anallyl or benzyl group, and R is an alkyl group having 1-5 carbon atoms,a hydroxyalkyl, dimethylaminoalkyl or methylthioalkyl group having 2-6carbon atoms in the alkyl part and having the heteroatom bound in aposition other than the 1 position, or an alkenyl group having 3-5carbon atoms other than a 1-alkenyl group, as bases and pharmaceuticallyacceptable acid addition salts thereof, which compounds are potentneuropharmacological agents. Thus said compounds are active aspresynaptic dopamine receptor agonists when administered to animalsincluding man. Said compounds are thus useful for treatment of disordersin the central nervous system, especially psychotic disorders in man.

In particular compounds of the above formula wherein R representsn-propyl are described. EP-Al-0030526 refers to and covers in generalthe pure enantiomers as well as mixtures thereof. However, theenantiomers are not specifically disclosed.

In Acta Pharmaceutica Suecica Suppl. 1983:1 p. 130-137 and 145-153 thepharmacological properties of the (-) and (+) enantiomers of thecompound ##STR6## are described.

In European Patent Application No. 83850084.1, enantiomers of compoundsof the formula ##STR7## are described wherein Y is OH, R¹ COO, R² R³NCOO or R⁴ O. In compounds wherein Y is R² R³ NCOO R² is hydrogen, analkyl group having 1-5 carbon atoms, a phenethyl, benzyl or phenyl groupwhich may be mono- or disubstituted in the aromatic part with a methyl,methoxy, hydroxy, nitro or cyano group or a halogen, R³ is H, an alkylgroup having 1 to 5 carbon atoms or a phenyl group or R² and R³ togetherwith the nitrogen atom form a 5, 6 or 7 membered ring that may contain 1to 3 double bonds and/or 1 or 2 further heteroatoms selected from N, Oand S. Specifically described in either of the two European patentapplications above is i.a. a compound wherein Y is ##STR8##

DISCLOSURE OF INVENTION

According to the present invention it has been found that novelcompounds of the formula ##STR9## wherein n is 1 or 2, Y is OH, R¹ COO,R² R³ NCOO-- or R⁴ O whereby R¹ is an alkyl group having 1-5 carbonatoms or a possibly substituted phenyl group, R² is an alkyl grouphaving 1-5 carbon atoms, a phenethyl, benzyl or phenyl group, R³ is H oran alkyl group having 1-5 carbon atoms, and R⁴ is an allyl or benzylgroup, and R is an alkyl group having 1-5 carbon atoms, a hydroxyalkyl,dimethylaminoalkyl or methylthioalkyl group having 2-6 carbon atoms inthe alkyl part and having the heteroatom bound in a position other thanthe 1 position, an alkenyl group having 3-5 carbon atoms other than a1-alkenyl group, as bases and pharmaceutically acceptable acid additionsalts thereof, are potent neuropharmacoloqical agents. Thus saidcompounds are active as presynaptic dopamine receptor agonists whenadministered to animals including man. The compounds are thus useful fortreatment of disorders in the central nervous system, especiallypsychotic disorders in man. Further, among the compounds of theinvention are compounds having a positive inotropic cardiac effect,substantially lacking chronotropic effect. Such compounds are useful fortreatment of cardiac insufficiency.

An alkyl group may be a straight alkyl group or a branched alkyl grouphaving at least 3 carbon atoms.

A possibly substituted phenyl group R¹ may be a phenyl,2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or4-alkanoyloxyphenyl group with the formula ##STR10## wherein R⁵ is analkyl group having 1-6 carbon atoms.

According to the present invention it has also been found that the pureenantiomeric forms of compounds of the formula ##STR11## wherein Y isOH, R¹ COO, R² R³ NCOO-- or R⁴ O whereby R¹ is an aliphatic hydrocarbonresidue having 1-17 carbon atoms, a phenyl, 2,6-dimethylphenyl or 3- or4-hydroxyphenyl group or a 3- or 4-alkanoyloxyphenyl group with theformula ##STR12## wherein R⁵ is an alkyl group having 1-6 carbon atoms,or R¹ is a group ##STR13## wherein R⁶ is hydrogen, an alkyl group having1 to 5 carbon atoms or a phenyl group, R⁷ is hydrogen, an alkyl grouphaving 1 to 5 carbon atoms or an acyl group and R⁸ is hydrogen or analkyl group having 1 to 5 carbon atoms, R² is hydrogen, an alkyl grouphaving 1 to 5 carbon atoms, a phenethyl, benzyl or phenyl group whichmay be mono- or disubstituted in the aromatic part with a methyl,methoxy, hydroxy, nitro or cyano group or a halogen, R³ is H, an alkylgroup having 1 to 5 carbon atoms or a phenyl group or R² and R³ togetherwith the nitrogen atom form a 5, 6 or 7 membered ring that may contain 1to 3 double bonds and/or 1 to 2 further heteroatoms selected from N, Oand S, and R⁴ is an allyl or benzyl group, said enantiomer having thesame absolute configuration at the asymmetric carbon atom.sup.(*) asthat of the (-)-enantiomer of the compound of formula 1 wherein Y is OH,as bases and pharmaceutically acceptable acid addition salts thereof,possess unexpected valuable therapeutical properties in addition tothose previously described.

The (-)-enantiomer of the compound of the formula 1 wherein Y is OH isthe levo rotameric form. Compounds of the invention having Y other thanOH have the same absolute configuration as said (-)-enantiomer, it beingunderstood that said latter compounds are not necessarily the (-) orlevo rotameric forms.

In the pure enantiomers of the invention Y is in particular OH, R¹ COO,R² R³ NCOO-- or R⁴ O whereby R¹ is an alkyl group having 1-5 carbonatoms or a phenyl, 2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group ora 3- or 4-alkanoyloxyphenyl group with the formula ##STR14## wherein R⁵is an alkyl group having 1-6 carbon atoms R² is an alkyl group having1-5 carbon atoms, a phenethyl, benzyl or phenyl group, R³ is H or analkyl group having 1-5 carbon atoms, and R⁴ is an allyl or benzyl group.By X-ray crystallography the absolute configuration of the(-)-enantiomer of the compound of formula 1 wherein Y is OH has beendetermined to be the S configuration. Thus, the compounds of theinvention according to formula 1 all have S configuration.

An alkyl group may be a straight alkyl group or a branched alkyl grouphaving at least 3 carbon atoms. An acyl group R⁷ is a formyl, acetyl,benzoyl, methoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl group. Analiphatic hydrocarbon residue R¹ may be saturated or unsaturated.

According to the present invention it has also been found that compoundsof the formula ##STR15## wherein R² is n-propyl, isopropyl, tert. butylor one of the groups ##STR16## and R³ is hydrogen; or R² and R³ are eacha n-propyl, isopropyl or tert. butyl group; or R² and R³ together formthe group--(CH₂)₅ --as bases and pharmaceutically acceptable acidaddition salts thereof possess unexpected valuable therapeuticalproperties.

Symbols for numbers, atoms or groups referred to below have the broadestmeaning previously assigned unless specified otherwise.

Both organic and inorganic acids can be employed to form non-toxicpharmaceutically acceptable acid addition salts of the compounds of thisinvention. Illustrative acids are sulfuric, nitric, phosphoric,hydrochloric, citric, acetic, lactic, tartaric, pamoic,ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric,maleic and benzoic acid. These salts are readily prepared by methodsknown in the art.

In a restricted embodiment the invention is related

to compounds of the formula I above wherein n is 1 or 2, Y is OH, R¹COO-- or R² R³ NCOO--, whereby R¹ is an alkyl group having 1-5 carbonatoms, or a phenyl group, and R² is an alkyl group having 1-5 carbonatoms, a phenethyl, benzyl or phenyl group, and R³ is H or an alkylgroup having 1-5 carbon atoms, and R is an alkyl group having 1-5 carbonatoms, a hydroxyalkyl group having 2-6 carbon atoms in the alkyl partother than a 1-hydroxyalkyl group, an alkenyl group having 3-5 carbonatoms other than a 1-alkenyl group.

According to a preferred embodiment the invention is related tocompounds of the formula I wherein n is 2 and Y and R are as specifiedabove.

Preferred compounds are those wherein Y is OH or R¹ COO or R⁴ O. Furtherpreferred are compounds wherein R is an alkyl group having 3-5 carbonatoms.

In another preferred embodiment the invention is related to pureenantiomeric compounds of the formula 1 as defined above wherein Y isOH, R¹ COO-- or R² R³ NCOO--, whereby R¹, R² and R³ are as definedabove.

Compounds to be specifically mentioned are:

(-)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine,

(-)-N-n-propyl-3-[3-(4-pivaloyloxybenzoyloxy)phenyl]piperidine,

(-)-N-n-propyl-3-(3-allyloxyphenyl)piperidine,

(-)-3-(3-decanoyloxyphenyl)-1-propylpiperidine,

S-3-(3-pivaloyloxyphenyl)-N-n-propylpiperidine,

S-3-(3-acetoxyphenyl)-N-n-propylpiperidine,

S-3-(3-benzyloxyphenyl)-N-n-propylpiperidine, S-3-(3-N',N'-dimethylcarbamoyloxyphenyl)-N-n-propylpiperidine,

S-3-(3-N'-phenylcarbamoyloxyphenyl)-N-n-propylpiperidine,

and S-3-(3-N'-benzyloxycarbonylalanylphenyl)-N-n-propylpiperidine.

The compounds of the invention contain an asymmetric carbon atom in theheterocyclic ring moiety. The therapeutic properties of the compoundsmay to a greater or lesser degree be ascribed to either or both of thetwo enantiomers occurring. Thus the pure enantiomers as well as mixturesthereof are within the scope of the invention.

The invention takes into consideration that compounds which structurallydeviate from the formula I, after administration to a living organism,may be transformed to a compound of the formula I and in this structuralform exert their effects. This consideration is a further aspect of theinvention. Likewise, certain compounds of formula I may be metabolizedinto other compounds of formula I before exerting their effect.Compounds of the invention wherein Y is R¹ COO. R² R³ NCOO or R⁴ O arethus believed to exert their main activity after metabolism to compoundswherein Y is OH.

In particular, the most valuable therapeutical properties have beenfound to reside in compounds having S configuration at the asymmetriccarbon atom(*) which thus constitute a preferred embodiment of theinvention.

METHODS OF PREPARATION

The compounds of the invention may be obtained by one of the followingmethods constituting a further aspect of the invention.

I. New Substituted Phenylazacycloalkanes

(a) An ether or ester of the formula ##STR17## wherein R^(a) representsa hydrocarbon or acyl residue, preferably an alkyl group having 1-5carbon atoms, or an alkylcarbonyl group having 2-6 carbon atoms, and nand R are as defined above, may be cleaved to form a compound of formulaI wherein Y is a hydroxy group.

When R^(a) is a hydrocarbon residue the cleavage may be carried out bytreating the compound of the formula II with an acidic nucleophilicreagent such as aqueous HBr, or HI, HBr/CH₃ COOH, BBr₃, AlCl₃,pyridine-HCl or (CH₃)₃ SiI, or with a basic nucleophilic reagent such asCH₃ C₆ H₄ --S⁻ or C₂ H₅ --S³¹.

When R^(a) is an acyl residue the cleavage may be carried out byhydrolysis in an aqueous acid or base or by reduction, preferably byLiAlH₄.

(b) In a compound of the formula ##STR18## wherein Z represents SO₃ H,Cl or NH , a hydroxy group may be substituted for the group Z to theformation of a compound of formula I wherein Y represents a hydroxygroup. When Z is SO₃ H or Cl said reaction may be carried out bytreatment with a strong alkali under heating, suitably with an alkalimelt such as KOH when Z is SO₃ H, and with a strong aqueous alkali suchas NaOH or KOH when Z is Cl. When Z is NH₂ the reaction may be carriedout by treatment with aqueous nitrous acid to the formation of anintermediate diazonium compound which is then subjected to hydrolysis inwater.

(c) A compound of the formula I ##STR19## wherein Y is OH and R is otherthan hydroxyalkyl may be converted into a compound of the same formulawherein Y is R¹ COO, R² R³ NCOO or R⁴ O by treating the first mentionedcompound with an appropriate carboxylic acid halide R¹ COX or anhydride(R¹ CO)₂ O or with an appropriate carbamoyl halide R² R³ NCOX orisocyanate R² NCO in the presence of a base such as triethylamine orpyridine or an acid such as H₂ SO₄ or CF₃ COOH or with an appropriateallyl or benzyl halide R⁴ X in the presence of a base such astriethylamine, pyridine or potassium t-butoxide. X represents a halogen,preferably Cl or Br.

Alternatively, when conversion of Y=OH into R¹ COO is intended and R¹ is##STR20## a compound of formula I wherein Y is OH may first be convertedto a compound of formula I wherein Y is ##STR21## which is then treatedwith an appropriate carboxylic acid halide R⁵ COX or anhydride (R⁵ CO)₂O is the presence of a base or an acid.

(d) A compound of the formula ##STR22## may be converted into a compoundof formula I by alkylation of the nitrogen atom with an appropriatealkylating agent. Thus, the starting compound may be treated with analkyl, hydroxyalkyl, dimethylaminoalkyl, methylthioalkyl, alkenyl orbenzyl halide or tosylate RX₁, wherein X¹ represents Cl, Br, I or##STR23## in an organic solvent such as acetonitrile or acetone and inthe presence of a base such as K₂ CO₃ or NAOH, or the starting compoundmay be treated with a carboxylic acid NaBH₄ complex R^(b) COOH-NaBH₄,wherein R^(b) is defined by the relation R^(b) -CH₂ -equals R. To theformation of a compound of formula I wherein R is CH₃, which is notobtainable by the last-mentioned reaction, the alkylation reaction maybe carried out by treatment with a formaldehyde --Na(CN)BH₃ mixture. Tothe formation of a compound of formula I wherein R is hydroxyalkyl,dimethylaminoalkyl or methylthioalkyl the synthesis may also be carriedout by alkylation with an appropriate dihaloalkane giving amonohaloalkyl derivative of I followed by acid or alkaline hydrolysisand reaction with dimethylamine or CH₃ S.sup.θ. Especially, to theformation of a compound of formula I wherein R is 2-hydroxyalkyl, thealkylation may also be carried out by reaction with a 1,2-epoxyalkane.

(e) An amide- or imida- containing compound of the formula ##STR24##wherein M¹ and M² are the same or different and each represents --CH₂ --or ##STR25## C=O, and M³ is ##STR26## when M¹ and M² are both --CH₂ --,and in other case M³ is R. R^(c) is H, an alkyl or alkoxyl groupcontaining 1-4 carbon atoms, a hydroxyalkyl, dimethylaminoalkyl ormethylthioalkyl group containing 1-5 carbon atoms, or an alkenyl groupcontaining 2-4 carbon atoms, and R^(d) is H, R¹ CO, allyl or benzyl maybe converted into a compound of the formula I wherein Y is a hydroxy,allyl or benzyl group by reduction of the amide or imide function, andthe ester function R¹ COO if present. Thus the compound of formula IVmay be treated with a reducing agent, preferably a hydride reducingagent such as LiAlH₄ or BH₃ in an etheral solvent or a metal reducingagent such as Na in an alcoholic solvent such as n-butanol.

(f) A compound of the formula ##STR27## wherein R^(e) is H or benzyl andwherein R is an alkyl or hydroxyalkyl, dimethylaminoalkyl ormethylthioalkyl group as further defined above, may be converted eitherby direct reduction or by first elimination of the tertiary alcohol toan intermediary 1-cycloalkenyl compound and then reduction into acompound of formula I wherein Y is Oh and R is as just defined. Thereduction may preferably be carried out by catalytic hydrogenation witha catalyst such as Pd or PtO₂, and the elimination reaction by heatingin the presence of an acid.

(h) A compound of the formula ##STR28## wherein Y¹ is benzyloxy or Y,wherein Y is as originally defined, however, other than O-allyl, and Ris an alkyl group containing 1-5 carbon atoms or a hydroxyalkyl,dimethylaminoalkyl or methylthioalkyl group containing 2-6 carbon atomsand having the heteroatom bound in a position other than the 1-position,may be converted by reduction into the corresponding compound of formulaI wherein n is 2. When Y¹ is benzyloxy a compound of formula I wherein Yis OH is obtained. The reduction may preferably be carried out bycatalytic hydrogenation using a catalyst such as PtO₂, or by reductionwith NaHB₄ followed by catalytic hydrogenation.

(i) A compound according to the formula ##STR29## wherein one of thegroup Z¹ and Z² is a leaving group, X and the other is NHR, or Z¹ and Z²are both leaving groups X, and X is a leaving group such as Cl, Br, I or--OSO₂ C₆ H₄ CH₃, may be converted to a compound of formula I wherein Yis OH by treating the compound of formula VIII, or when one of Z¹ and Z²is NHR an acid addition salt thereof, with a base such as (C₂ H₅)₃ N orK₂ CO₃, whereby the compound of formula VIII is treated together with anequivalent amount of an amine R--NH₂ or an acid addition salt thereofwhen Z¹ and Z² are both X. The conversion is carried out in a solventsuch as tetrahydrofuran, dioxan or acetonitrile, if necessary withsimultaneous or subsequent heating of the mixture.

Free bases formed may subsequently be converted into their acid additionsalts, and acid addition salts formed may subsequently be converted intothe corresponding bases or other acid addition salts.

II. New Enantiomers of substituted phenylazacycloalkanes

The compounds of the invention may be obtained by one of the followingmethods constituting a further aspect of the invention.

(j) A pure enantiomer of an ether or ester of the formula ##STR30##having the appropriate absolute configuration at the asymmetric carbonatom(*), wherein R^(a) represents a hydrocarbon or acyl residue,preferably an alkyl group having 1-5 carbon atoms, or an alkylcarbonylgroup having 2-6 carbon atoms defined above, may be cleaved to form thecompound of formula 1 wherein Y is a hydroxy group, in the desired(-)-enantiomeric form.

When R^(a) is a hydrocarbon residue the cleavage may be carried out bytreating the compound of formula 2 with an acidic nucleophilic reagentsuch as aqueous HBr, or HI, HBr/CH₃ COOH, BBr₃, AlCl₃, pyridine-HCl or(CH₃)₃ SiI, or with a basic nucleophilic reagent such as CH₃ C₆ H₄ -S⁻or C₂ H₅ -S⁻.

When R^(a) is an acyl residue the cleavage may be carried out byhydrolysis in an aqueous acid or base or by reduction, preferably byLiAlH₄.

(k) In a pure enantiomer of a compound of the formula ##STR31## havingthe appropriate absolute configuration at the asymmetric carbon atom(*),wherein Z represents SO₃ H, Cl or NH₂, a hydroxy group may besubstituted for the group Z to the

formation of a compound of formula 1 wherein Y represents a hydroxygroup and in the desired (-)-enantiomeric form. When Z is SO₃ H or Clsaid reaction may be carried out by treatment with a strong alkali underheating, suitably with an alkali melt such as KOH when Z is SO₃ H, andwith a strong aqueous alkali such as NaOH or KOH when Z is Cl. When Z isNH₂ the reaction may be carried out by treatment with aqueous nitrousacid to the formation of an intermediate diazonium compound which isthen subjected to hydrolysis in water.

(1) The (-)-enantiomeric form of the compound of formula 1 ##STR32##wherein Y is OH may be converted into a compound of the same formula andthe same absolute configuration at the asymmetric carbon atom(*) whereinY is R¹ COO, R² R³ NCOO or R⁴ O by treating the first mentioned compoundwith an appropriate carboxylic acid halide R¹ COX or anhydride (R¹ CO)₂O or with an appropriate carbamoyl halide R² R³ NCOX or isocyanate R²NCO in the presence of a base such as triethylamine or pyridine or anacid such as H₂ SO₄ or CF₃ COOH or with an appropriate allyl or benzylhalide R⁴ X in the presence of a base such as triethylamine, pyridine orpotassium t-butoxide. X represents a halogen, preferably Cl or Br.

Alternatively, when conversion of Y=OH into R¹ COO is intended and R¹ is##STR33## a compound of formula 1 wherein Y is OH may first be convertedto a compound of formula 1 wherein Y is ##STR34## COO⁻ which is thentreated with an appropriate carboxylic acid halide R⁵ COX or anhydride(R⁵ CO)₂ O in the presence of a base or an acid.

(m) A pure enantiomer of a compound of the formula ##STR35## having theappropriate absolute configuration may be converted into a compound offormula 1 having the desired absolute configuration at the asymmetriccarbon atom.sup.(*) by alkylation of the nitrogen atom with anappropriate alkylating agent. Thus the starting compound may be treatedwith a n-propyl halide or tosylate RX¹, wherein X¹ represents Cl, Br, Ior OSO₂ ##STR36## CH₃ in an organic solvent such as acetonitrile oracetone and in the presence of a base such as K₂ CO₃ or NaOH, or thestarting compound may be treated with a n-propionic acid NaBH₄ complex.

(n) A pure enantiomer of a carbonyl compound of the formula ##STR37##having the appropriate absolute configuration, wherein M¹ and M² are thesame or different and each represents --CH₂ -- or ##STR38## and thedashed lines represent bonds, one of which, when adjacent to a group##STR39## may be open and replaced by hydrogen atoms, and M³ is##STR40## when M¹ and M² are both --CH₂ --, and in other cases M³ isn-C₃ H₇, and R^(d) is H or R¹ CO, may be converted into a compound ofthe formula 1 having the desired absolute configuration at theasymmetric carbon atom.sup.(*) and wherein Y is a hydroxy, allyloxy orbenzyloxy group by reduction of the amide or imide function, and theester function R¹ COO if present.

Thus the compound of formula 5 may be treated with a reducing agent,preferably a hydride reducing agent such as LiAlH₄ or BH₃ in an etheralsolvent or a metal reducing agent such as Na in an alcoholic solventsuch as n-butanol when ring closure is not required When one of thedashed lines in formula 5 represents an open bond, the reductioncomprises a ring closure in a compound of the formula ##STR41## and maybe done by catalytic hydrogenation.

(o) A compound of the formula ##STR42## with either a C₂ -C₃ or a C₃ -C₄double bond and wherein R^(e) is H or benzyl may be converted byreduction into a compound of formula 1 wherein Y is OH and having thedesired (-)-enantiomeric form. The reduction may preferably be carriedout by catalytic hydrogenation with an appropriate chiral homogenousphase catalyst such as a Rh-complex with chiral phosphines. If required,the product may be purified to obtain only the desired enantiomer in apure form.

(p) A pure enamtiomer of a compound according to the formula ##STR43##having the appropriate absolute configuration, wherein one of the groupZ¹ and Z² is a leaving group X and the other is NH(CH₂)₂ CH₃ or Z¹ andZ² are both leaving groups X, and X is a leaving group such as Cl, Br, Ior --OSO₂ C₆ H₄ CH₃, may be converted to a compound of formula 1 whereinY is OH and having the desired (-)-enantiomeric form by treating thecompound of formula 7, or when one of Z¹ and Z² is NH(CH₂)₂ CH₃ an acidaddition salt thereof, with a base such as (C₂ H₅)₃ N or K₂ CO₃, wherebythe compound of formula 7 is treated together with an equivalent amountof an amine CH₃ (CH₂)₂ --NH₂ or an acid addition salt thereof when Z¹and Z² are both X. The conversion is carried out in a solvent such astetrahydrofuran, dioxane or acetonitrile, if necessary with simultaneousor subsequent heating of the mixture.

(q) A racemic mixture or a mixture partly enriched on one of theenantiomers of a compound of formula ##STR44## may be subjected to aenantiomeric separation to obtain the desired enantiomer of compound 1.This may be done by methods known in the art. These methods includerecrystallization of diastereomeric salts with pure enantiomers of acidssuch as tartaric acid, O,O'-dibenzoyltartaric acid, mandelic acid andcamphor-10-sulphonic acid.

Free bases formed may subsequently be converted into their acid additionsalts, and acid addition salts formed may subsequently be converted intothe corresponding bases or other acid addition salts.

(r) A compound of the formula ##STR45## may be converted into a compoundof formula bI by treating the first-mentioned compound with anappropriate carbamic acid derivative R² R³ NCOX or aminoformaldehyde R²R³ NCOH or isocyanate R² NCO or isocyanide R² N═C, whereby X representsa leaving group such as a halogen preferably Cl or Br or a metal sulfiteSO₃ Me or the group R² R³ N

The reaction with a carbamoyl halide or isocyanate is done in thepresence of a base such as triethylamine or pyridine or an acid such asH₂ SO₄ or CF₃ COOH. The reaction with the isocyanide is done in thepresence of a halogen or halogen generator such as Br₂, Cl₂ orN-bromo-succinimide. The reaction with the aminoformaldehyde may becarried out in the presence of an oxidant such as lead tetraacetate.

The isocyanate R² NCO may be added as such or formed in situ asdescribed below.

Compound bII may be present in the form of the phenol or a metal saltthereof e.g., the sodium salt.

When X represents the group R² R³ N the reaction is carried out at anelevated pressure and temperature.

(s) A compound of the formula ##STR46## wherein Y is a leaving groupobtainable by reaction of phosgene or a phosgene derivative with aphenol of formula bII above, may be reacted with an amine of the formula

    R.sup.2 R.sup.3 NH

to the formation of a compound of formula bI Examples of phosgenederivatives are ##STR47## wherein φ is a phenyl group. Examples ofgroups Y are thus chlorine or a group derived from the phosgenederivative employed.

(t) A compound of the formula ##STR48## may be converted into a compoundof formula bI by alkylation of the nitrogen atom with an appropriatealkylating agent. Thus the starting compound may be treated with an-propyl halide or tosylate RX¹, wherein X¹ represents Cl, Br, I or##STR49## in an organic solvent such as acetonitrile or acetone and inthe presence of a base such as K₂ CO₃ or NaOH, or the starting compoundmay be treated with a n-propionic acid NaBH₄ complex.

When possible and desired a reactant may be inserted as a salt, such asa phenolic metal salt or a quaternary ammonium acid addition salt, inthe place of the phenol or amine described above.

To obtain a pure enantiomer of a compound of formula bI, a racemicmixture partly enriched on one of the enantiomers of a compound of theformula I may subsequently be subjected to enantiomeric separation toobtain the desired enantiomer of compound bI. This may be done bymethods known in the art. These methods include recrystallization ofdiastereomeric salts with pure enantiomers of acids such as tartaricacid, O,O-dibenzoyltartaric acid, mandelic acid and camphor-10-sulphonicacid.

The above methods are equally useful for preparing compounds describedin European Patent Application No. 83850084.1 as presented above whereinY is R² R³ NCOO. A further embodiment of the present invention is thuspreparation of comoounds described in the above-identified patentapplication by one of the above methods.

PREPARATION OF STARTING MATERIALS

Starting materials for the methods of preparation described above may beobtained by several methods known in Section I in the art or describedbelow.

The starting material for method (a) according to formula II above maybe prepared by one of the following methods: ##STR50##

A compound of formula IX, wherein R^(a) is an alkyl group having 1-5carbon atoms, is reduced e.g. with LiAlH₄. In the compound X formed, agroup R may then be introduced in analogy with the procedure of method(d) above or by modification of the first step in analogy with method(e) above. ##STR51##

In a compound of formula XI, obtainable by method (E2) below, themethoxy group is split off with HBr, whereupon a protective group R^(a)being an alkyl group having 1-5 carbon atoms or an acyl group having 2-6carbon atoms, is substituted in the hydroxy group by reaction with ahalide R^(a) X in the presence of a base. The compound thus formed isthen hydrogenated to the formation of a compound of formula II wherein nis 2 and R^(a) is as just defined with previous (method H) or subsequent(method Al) introduction of a group R.

The starting material for method (b) may be prepared by one of thefollowing methods. ##STR52##

In a compound of formula XIII a group R may be introduced as previouslydescribed whereupon the compound is treated with Cl₂ or H₂ SO₄ to theformation of an isomeric mixture XIV, from which the compound IIIwherein Z is Cl or SO₃ H is obtained by chromatographic separation.##STR53##

The compound of formula XV is hydrogenated under acidic conditions inthe presence of PtO₂ to give a phenylpiperidine which is N-acylated withan appropriate carboxylic acid chloride R^(f) COCl wherein R^(f) is analkyl group having 1-4 carbon atoms or an ethoxy group, in the presenceof a base such as triethylamine, giving an amide, which is subjected tomild acid or basic hydrolysis of the ester function giving a compoundXVI. Said compound XVI is treated with ClCOOC₂ H₅ and triethylamine andthen with sodium azide giving a carboxylic acid azide which on heatinggives the isocyanate XVII. The isocyanate is treated with an excess ofboiling benzyl alcohol giving a carbamate which is then hydrogenated inthe presence of Pd/C to give a compound XVIII. A compound of formula IIIwherein Z is NH₂ and n is 2 is then formed by subjecting the amide groupof compound XVIII to splitting with an aqueous acid or base when anN-unsubstituted compound is desired, to reduction with e.g., LiAlH₄ whenR= an alkyl group having 2-5 carbon atoms is desired. When R=CH₃ isdesired a compound XVIII wherein R^(f) is an ethoxy group may be treatedwith LiAlH₄.

The starting materials for method (e) may be prepared by one of thefollowing methods ##STR54##

A compound of formula XIX may be formed by N-acylation of acorresponding compound of formula X, preparable according to Al above,with an acid chloride R^(c) COCl in the presence of a base. The etherfunction of compound XIX is then cleaved with BBr₃ to the formation of acompound of formula IV wherein M¹ and M² are both --CH₂ -- and R^(d) isH. If desired the hydroxy group may then be acylated with an acylchloride to form a compound of formula IV wherein R^(d) is R¹ CO, oralkylated with an allyl or benzyl halide to form a compound of formulaIV wherein R^(d) is allyl or benzyl. ##STR55##

A compound of formula XX wherein R² is alkyl having 1-5 carbon atoms isreacted with I(CH₂)_(n) COOC₂ H₅, or alternatively when n=2 is desiredwith CH₂ ═CH--COOC₂ H₅, in the presence of a base to the formation of acompound of formula XXI. When n=1 is desired compound XXI may beprepared by the following route. ##STR56##

The compound obtained by reaction of the alkoxybenzaldehyde withdiethylmalonate is reacted with KCN in ethanol to the formation of acompound XXI wherein n is 1.

The compound XXI obtained by one of said routes is then converted into acompound of formula IV along the following route. ##STR57##

Compound XXI is treated with hydrogen in the presence of a catalyst suchas Raney nickel to the obtention of compound XI, in which a substituentis introduced at the nitrogen atom, if required in the end compound, bymeans of a halide RX. The ether function is then cleaved with BBr₃giving a compound IV wherein R^(d) is H and M¹ is --CH₂ --and M² is##STR58## and, if required in compound IV, the hydroxy group is acylatedwith an acyl chloride R¹ COCl in the presence of a base, or alkylatedwith an allyl or benzyl halide to form a compound of formula IV whereinR^(d) is allyl or benzyl. ##STR59##

A compound of formula XXIV is reacted with I(CH₂)_(n) CN, oralternatively when n═2 is desired with CH₂ ═CH--CN, in the presence of abase, to the formation of a compound XXV. The subsequent route forpreparation of the compound IV wherein M¹ is ##STR60## and M² is --CH₂-- is completely analogous to the route XXI to IV described above.##STR61##

A compound of formula IV wherein M¹ is ##STR62## M² is --CH₂ --, M³ isR, R^(d) is H and n is 1 or 2 may be prepared by oxidation of a compoundof formula VI above e.g. with Br₂. ##STR63##

A compound of formula XXI is heated with an aqueous acid to theformation of a dicarboxylic acid XXVI, which is then reacted with aceticacid anhydride. Heating of the resulting cyclic anhydride with an amineR--NH₂ yields an imide XXVII, in which the ether function is cleavedwith BBr₃ giving a compound IV wherein R^(d) is H and M¹ and M² are both##STR64## and, if required, the hydroxy group is acylated to theformation of compound IV, wherein R^(d) is R¹ CO, or alkylated with anallyl or benzyl halide to form a compound of formula IV wherein R^(d) isallyl or benzyl.

The starting material for method (f) may be prepared by the followingmethod. ##STR65##

A Grignard reaction with compounds XXVIII and XXIX produces compound V.The compound XXIX may be prepared by reacting a compound of the formula##STR66## with an alkyl bromide RBr in the presence of a base such as K₂CO₃ when an alkyl group R is required.

Starting material for method (h) may be prepared by the followingmethod. ##STR67##

When a group Y¹ other than hydroxy is required, such a group isintroduced by reaction of a compound XII with an appropriate acyl,carbamoyl, benzyl or allyl chloride in the presence of a base. Thepyridyl nitrogen is then reacted with a hydrogen halide or alkyl halideRX¹ (X¹ =Br or I) to the formation of an ion VII.

Starting materials for method (i) may be prepared by one of thefollowing methods. ##STR68##

A compound of formula XXI, obtainable according to method (E2), isreduced with LiAlH₄ to the formation of compound XXX, which isN-substituted with a halide RX¹, wherein X¹ is a halogen, in thepresence of a base. In the compound obtained the ether function iscleaved with aqueous HBr to the formation of a compound XXXI. A leavinggroup X is then introduced to the formation of compound VIII, wherein Z¹is NHR and Z² is X, by reaction with thionyl chloride, whereby X=Cl isobtained, or with an acid HX. ##STR69##

A compound of formula XXV, obtainable according to method (E3), isconverted into a compound of formula VIII, wherein Z¹ is X and Z² isNHR, in a manner analogous to the conversion XXI to VIII under (I1)above. ##STR70##

A compound of formula XXVI, obtainable according to method (E4), isreduced with LiAlH₄. In the resulting compound the ether function iscleaved with aqueous HBr to the formation of a compound of formulaXXXII. In compound XXXII two leaving groups X are introduced to theformation of a compound VIII, wherein Z¹ and Z² are each X, by reactionwith thionyl chloride, whereby X=Cl is obtained, or with an acid HX.

INTERMEDIATES

Some of the intermediates or starting materials mentioned above and thepreparation thereof are known. However, certain intermediates orstarting materials are novel and constitute a further aspect of theinvention. Thus in one aspect the invention is related to novelcompounds of the formula ##STR71## wherein Z³ is R or R⁶ CO wherein R⁶is an alkyl or alkoxy group containing 1-4 carbon atoms or an alkenylgroup with 2-4 carbon atoms, R⁷ is an alkyl group with 1-5 carbon atoms,an allyl or benzyl group and n is 1 or 2 provided that Z³ is other thanmethyl and ethyl when n is 2 and R⁷ is CH₃, as well as to acid additionsalts (where possible) of said compounds, and to the methods forpreparing said compounds or salts.

Starting materials for the methods of preparation described in SectionII above may be obtained by several methods known in the art inparticular in EP-Al-0 030 526, and/or described below.

The starting material for method (j) according to formula 2 above may beprepared by the following method: ##STR72##

A compound of formula 8 (racemic mixture) wherein R^(a) is an alkylgroup having 1-5 carbon atoms or an acyl group having 2-6 carbon atomsis resolved either by first conversion into the N-benzyl analogue 9followed by recrystallization of the (+)-tartaric acid salt anddebenzylation by hydrogenation, or (when R^(a) is alkyl) by firstconversion into the (-)-O-methylmandelic acid amide (10) followed bychromatographic separation of the two diastereomers and cleavage byKOBu^(t) in tetrahydrofuran with traces of water. The enantiomer withthe desired absolute configuration 11 is then alkylated bypropionylation followed by LiAlH₄ reduction to the formation of compound2 having the appropriate absolute configuration at the asymmetriccarbon.sup.(*) atom.

The starting material for method (k) may be prepared by the followingmethod: ##STR73##

In a compound of formula 12 a group n--C₃ H₇ may be introduced aspreviously described with previous (method j) or subsequent (method q)resolvation into the desired enantiomer whereupon the compound istreated with Cl₂, H₂ SO₄ or HNO₃ followed by reduction to the formationof an isomeric mixture 8, from which the compound 3 wherein Z is Cl, SO₃H or NH₂ is obtained by chromatographic separation.

(D) The starting materials for method (m) may be prepared according tomethod (j) above.

A starting material for method (n) may be prepared by the followingmethod ##STR74##

A compound of formula 15 may be formed by N-acylation of a correspondingcompound of formula 14, preparable according to j above, with C₂ H₅ COClin the presence of a base. The ether function of compound 15 is thencleaved with BBr₃ to the formation of a compound of formula 5 wherein M¹and M² are both --CH₂ --and R^(d) is H. If desired the hydroxy group maythen be acylated with an acyl chloride to form a compound of formula 5wherein R^(d) is R¹ CO, or alkylated with an allyl or benzyl halide toform a compound of formula 5 wherein R^(d) is allyl or benzyl.

The starting material for method (o) may be prepared by the followingmethod. ##STR75##

A Grignard reaction with compounds 16 and 17 followed by elimination ofthe hydroxy-group produces compound 6.

Starting materials for method (p) may be prepared by enantiomericseparation of the corresponding racemate or a precursor thereof.

Thus, the compound of formula bII and the compound of formula bV aboveare obtainable as described in EP-Al-0030526. To obtain said compound inpure enantiomeric form enantiomer separation is carried out on theracemic compound or a precursor thereof as further described in EuropeanPatent Application No. 83850084.1.

The isocyanate employed by method (r) may be formed in situ by one ofthe reactions ##STR76## whereby φ represents phenyl.

PHARMACEUTICAL PREPARATIONS

Pharmaceutical preparations of the compounds of the invention constitutea further aspect of the invention. For such preparations reference ismade to pages 23 to 25 of EP-A10030526 which is incorporated byreference herein.

In clinical practice the compounds of the present invention willnormally be administered orally, rectally, or by injection, in the formof pharmaceutical preparations comprising the active ingredient eitheras a free base or as a pharmaceutically acceptable non-toxic, acidaddition salt, e.g. the hydrochloride, lactate, acetate, sulfamate, andthe like, in association with a pharmaceutically acceptable carrier.

Accordingly, terms relating to the novel compounds of this invention,whether generically or specifically, are intended to include both thefree amine base and the acid addition salts of the free base, unless thecontext in which such terms are used, e.g. in the specific examples,would be inconsistent with the broad concept. The carrier may be asolid, semisolid or liquid diluent or capsule. These pharmaceuticalpreparations constitute a further aspect of this invention. Usually theactive substance will constitute between 0.1 and 99% by weight of thepreparation, more specifically between 0.5 and 20% by weight forpreparation intended for injection and between 0.2 and 50% by weight forpreparations suitable for oral administration.

Pharmaceutical preparations containing a compound of the invention in asolid form of dosage units for oral application may preferably containbetween 2 and 50% by weight of the active substance; in suchpreparations the selected compound may be mixed with a solid fine graincarrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such aspotato starch, corn starch or amylopectin, cellulose derivatives, orgelatin and a lubricant such as magnesium stearate, calcium stearate,polyethylene glycol waxes, and the like, and then compressed to formtablets. If coated tablets are required, the cores, prepared asdescribed above, may be coated with a concentrated sugar solution whichmay contain, e.g. gum arabic, gelatin, talcum, titanium dioxide, and thelike. Alternatively the tablet can be coated with a lacquer dissolved ina readily volatile organic solvent or mixture of organic solvents.Dyestuffs may be added to these coatings in order to readily distinguishbetween tablets containing different active substances or differentamounts of the active compound.

For the preparation of soft gelatin capsules (pearl-shaped closedcapsules) consisting of gelatin and, for example, glycerol, or similarclosed capsules, the active substance may be admixed with a vegetableoil. Hard gelatin capsules may contain granulates of the activesubstance in combination with solid, fine grain carriers such aslactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch,corn starch or amylopectin), cellulose derivatives or gelatin.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing from about 0.2% to about20% by weight of the active substance herein described, the balancebeing sugar and a mixture of ethanol, water, glycerol andpropyleneglycol. Optionally such liquid preparations may containcolouring agents, flavouring agents, saccharine andcarboxymethylcellulose as a thickening agent.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance preferably in a concentration of from about 0.5% toabout 10% by weight. These solutions may also contain stabilizing agentsand/or buffering agents and may conveniently be provided in variousdosage unit ampoules.

In therapeutical treatment the suitable daily doses of the compounds ofthe invention are 200-10,000 mg for oral application, preferentially1,000-6,000 mg, and 1-1,000 mg for parenteral application,preferentially 50-500 mg.

WORKING EXAMPLES

The following examples will further illustrate the invention.

Preparation of intermediates Example I1.N-Butyl-3-(3-methoxyphenyl)piperidine hydrochloride (Method Al and e)

Butyryl chloride (2.0 g, 0.019 mol) in dry toluene (5 ml) was slowlyadded to a solution of 3-methoxyphenylpiperidine (2.45 g, 0.013 mol) andtriethylamine (1.92 g, 0.013 mol) in dry toluene at 5° . The mixture wasstirred at room temperature for 30 min., whereupon the triethylammoniumchloride formed was filtered off and the solvent evaporated. The crudeN-butyryl-3-(3-methoxyphenyl)piperidine (2.82 g) dissolved in drytetrahydrofuran (30 ml) was added to a suspension of LiAlH₄ (2.0 g) indry tetrahydrofuran (30 ml) under nitrogen. After reflux for 3 h themixture was hydrolysed, the precipitate filtered off and the solventevaporated. The residue dissolved in light petroleum was passed throughan alumina column. (Alternatively the residue could be distilled invacuo.) The product was precipitated as the hydrochloride andrecrystallized from ethanol/ether yielding the pure product (3.6 g, 88%)mp 130-1° C.

Example I2. N-Propyl-3-(3-methoxyphenyl)pyrrolidine (Method Al and e)

3-(3-methoxyphenyl)pyrrolidine (8.86 g, 0.050 mol) and triethylamine(5.57 g, 0.055 mol) was dissolved in 500 ml of dry ether. The solutionwas cooled to 0° C and propionyl chloride (5.09 g, 0.055 mol) was addeddropwise with stirring. The reaction mixture was then allowed to acquireambient temperature, whereafter it was refluxed for 30 minutes.Triethylamine hydrochloride was filtered off, and the filtrate wasevaporated leaving 11.7 g (100%) of crudeN-propionyl-3-(3-methoxyphenyl)pyrrolidone, which was used in the nextreaction step without further purification. The crude amide (11.7 g,0.050 mol) was reduced with LiAlH₄ (2.85 g, 0.075 mol) in refluxingether (200 ml) for 24 hours. Workup of the reaction mixture afforded 10g of product, which upon distillation in vacuo yielded 9.1 g (83%) ofN-propyl-3-(3-methoxyphenyl)-pyrrolidine b.p. 85-86° C/O.1 mm Hg. MS:m/e 219 (M.sup. +, 12%) 190 (M--C₂ H₅, 100%).

ExampIe I3. N-Pentyl-3-(3-methoxyphenyl)piperidine (Method Al and d)

To a solution of 3-(3-methoxyphenyl)piperidine (3.92 g, 0.02 mol) in CH₃CN (100 ml), solid K₂ CO₃ (5 g) was added and then the mixture wasrefluxed. A solution of pentyliodide (4.5 g, 0.021 mol) in CH₃ CN (10ml) was added dropwise under 30 min. and then the mixture was refluxedfor an additional 30 min. The solid was filtered off from the cooledmixture, and the solvent evaporated giving an oil which waschromatographed on a silica gel column with methanol as eluant. Yield1.3 g (25%) of pure N-pentyl-3-(3-methoxyphenyl)piperidine (NMR) as anoil.

Example I4. N-Propyl-3-(3-methoxyphenyl) piperidine hydrochloride(Method Al and d)

NaBH₄ (6.08 g, 0.16 mol) was added portionwise under stirring to asolution of propionic acid (38 g, 0.51 mol) in dry benzene (150 ml). Thetemperature was kept below 15° C. for 2 h and then3-(3-methoxyphenyl)-piperidine (6.1 g, 0.032 mol) dissolved in drybenzene (100 ml) was added and the mixture was refluxed for 3 h. Thereaction mixture was allowed to reach room temperature and was thenextracted with 2.5 M NaOH (200 ml). The aqueous phase was extracted withbenzene, all the benzene phases mixed, dried (Na₂ SO₄) and the solventevaporated giving an oily residue (6.6 g). The product was precipitatedas hydrochloride and recrystallized from methanol/isopropyl etheryielding the pure product (6.2 g, 72%), mp. 191° C.

Example I6. N-Propyl-3-(3-methoxyphenyl)piperidine hydrobromide (MethodA2 and h)

3-(3-pyridinyl)methoxybenzene (3.0 g, 0.016 mol) and propyl bromide (2.0g) was dissolved in dry acetone (50 ml) and allowed to react at 110° C.in a high pressure steel vessel. After 20 h the reaction was interruptedand the solvent was evaporated. The residual quartenaryN-propyl-3-(3-methoxyphenyl) pyridinium bromide was hydrogenated (PtO₂)in methanol at r.t. and 760 mmHg. The H₂ -uptake ceased after 24 h. Thecatalyst was filtered off and the solvent evaporated. The hydrobromidewas recrystallized from ethanol/ether giving 2.63 g (70%) of the pureproduct, mp. 155-156° C.

Example I7. 3-(3-Pyridinyl)methoxybenzene (Method A2)

This substance was prepared by a dichlorobis-(triphenylphosphine)nickel(II) catalyzed reaction between 3-methoxyphenylmagnesium bromide (from50 g of 3-bromo-anisole and 5.9 g of Mg in THF) and 31.8 g of3-bromopyridine. Yield 23.1 g (62%), bp. 102° /0.15 mmHg, mp. (HCl)187.5-9° C.

Example I8. 3-(3-Methoxyphenyl)piperidine hydrochloride (Method A2 andh)

To a solution of 3-(3-pyridinyl)methoxybenzene (22.0 g, 0.099 mol) inmethanol (250 ml), PtO₂ (2 g) and conc. HCl (30 ml) were added and themixture was hydrogenated at 0.34 MPa in a Parr apparatus. After completehydrogenation, the catalyst was filtered off Most of the solvent wasevaporated, the residue was made alkaline with 1M NaOH and extractedwith ether. The ether-phase was dried (Na₂ SO₄) and the solventevaporated giving 18 g of the amine product. The hydrochloride was madeand then recrystallized from ethanol/ether yielding 20.9 g (93%), mp.137-138.5° C.

Example I9. N-n-Propyl-3-(3-aminophenyl)piperidine hydrochloride (MethodB2) 3-(3-Methylphenyl)-pyridine

3-(3-methylphenyl)-pyridine was prepared from 81.5 g (0.52 mol)3-bromopyridine and 120 g (0.70 mol) 3-bromo-toluene as described forthe preparation of 3-(3-methoxyphenyl)-pyridine. (Example I7.) B.p. 87°/0.05 mmHg. Yield 61.7 g (69%).

Methyl-3-(3-oyridyl)-benzoate

A mixture of 3-(3-methylphenyl)-pyridine (30 g, 0.177 mol), potassiumpermanganate (67.5 g, 0.427 mol) and water (825 ml) was refluxedovernight with stirring. The hot mixture was filtered, acidified (conc.HCl) and evaporated in vacuo. After drying in the air the solid wasdissolved in HCl-saturated methanol (2500 ml), the resulting solutionwas refluxed for 24 hours. The methanol was evaporated and the residuewas made alkaline with saturated potassium carbonate solution.Extraction with ether followed by drying (K₂ CO₃) and evaporation of theether gave an oil which was distilled in vacuo. The fraction distillingfrom 90° C. to 135° C. at 0.2 mm was then filtered through a SiO₂-column with ether as eluant. Evaporation of the ether gave the pureproduct (21 g, 55%) as a solid.

The hydrochloride was prepared by dissolving the amino-ester in etherfollowed by addition of HCl-saturated ether. The salt was recrystallizedfrom methanol/ether, mp. 208°-209° C.

3-(1-Propionylpiperidin-3-yl)-benzoic acid

A solution of the HCl-salt of methyl-3-(3-pyridyl)benzoate (5.54 g,0.022 mol) in methanol was hydrogenated (atm. pressure) at r.t. usingPtO₂ as catalyst. After filtration and evaporation the residue waspartitioned between a saturated potassium-carbonate solution and ether.The ether layer was dried (K₂ CO₃), cooled and treated withtriethylamine (2.23 g. 0.022 mol) and propionylchloride (2.05 g), 0.033mol). Stirring at r.t. for one hour followed by filtration andevaporation gave an oil which was eluated twice through an Al₂ O₃-column with ether. Evaporation of the ether gave 4.8 g of puremethyl-3-(1-propionylpiperdin-3-yl)benzoate as an oil, which could notbe crystallized.

A mixture of methyl-3-(1-propionylpiperidin-3-yl)benzoate (4.8 g, 0.17mol), sodium hydroxide pellets (5 g), methanol (80 ml) and water (20 ml)was stirred until TLC indicated that no starting material remained (4hours). The methanol was evaporated and the alkaline water layer waswashed with ether, acidified with hydrochloride acid and extracted withchloroform. Evaporation gave the product (4.0 g, 69% yield frommethyl-3-(3-pyridyl)-benzoate) as an oil which crystallized afterseveral weeks on standing. (Mp. 125°-126° C.)

N-propyl-3-(3-Aminophenyl)-piperidine hydrochloride

To a cooled (-10° C.) solution of 3-(1-propionylpiperidin-3-yl)benzoicacid (9.75 g, 0.036 mol) and triethylamine (3.56 g, 0.033 mol) inacetone (115 ml) ethyl chloroformate (4.34 g, 0.040 mol), was slowlyadded. After stirring at -10° C. for one and a half hour, a solution ofsodium azide (3 g, 0.046 mol) in water (10 ml) was added dropwise, andthe mixture was stirred at -10° C. for one hour more. The reactionmixture was poured into icewater and extracted with toluene. The tolueneextract was dried (MgSO₄) and heated until a small sample run on IRindicated that the reaction (the conversion of the acyl azide to theisocyanate) was complete. Evaporation of the toluene gave the isocyanateas an oil.

The isocyanate was boiled with benzyl alcohol (20 ml) until the reactionwas complete (IR; 24 hours). Evaporation of unreacted benzylalcohol gavean oil (1.5 g) which was dissolved in methanol and hydrogenated at r.t.and atmospheric pressure with 10% Pd/C as catalyst. Filtration andevaporation gave an oil which was further reacted with LiAlH₄ (1.0 g,0.026 mol) in tetrahydrofuran. Refluxing for 3 h followed by hydrolysisof the reaction mixture, filtration and evaporation of the solvent gavethe crude N-n-propyl-3-(3-aminophenyl)piperidine which was converted toits dihydrochloride by dissolving the base in methanol and saturatingthe solution with HCl. Evaporation of the methanol gave the salt as anoil. Yield: 0.40 g (4%, calculated on3-(1-propionylpiperidin-3-yl)benzoic acid). A sample of the oil wasreconverted to the base and dissolved in CDCl₃ for NMR (see table).

Preparation of intermediates Example I10.(+)-3-(3-Methoxyphenyl)piperidine hydrochloride (Method j).

(+-Dibenzoyl-D-tartaric acid (28.2 g, 0.075 mol) in hot methanol (350ml) was added to N-benzyl-3-(3-methoxyphenyl) piperidine (21.1 g, 0.075mol) in hot methanol (100 ml). After two days the salt that separatedwas recrystallized three times from methanol. The collected salt (8.3 g)was treated with 1M NaOH (250 ml) and the free amine was extracted withether (3×150 ml). The combined ether layers were dried (K₂ CO₃) and thesolvent evaporated. The residual amine was then passed through a shortalumina column with ether as eluant and then converted to thehydrochloride. One recrystallization from methanol-ether gave(-)-N-benzyl-3-(3-methoxyphenyl)-piperidine hydrochloride (3.8 g), m.p.164°-165° C; [α]²² D -43.1° (C 2.1, CH₃ OH).

(-)-N-benzyl-3-(3-methoxyphenyl)piperidine hydrochloride (3.8 g, 0.0120mol) was dissolved in ethanol (80 ml), 10% Pd/C was added and themixture was hydrogenated at room temperature and atmospheric pressure(28 h). The catalyst was removed (Celite) by filtration, the solvent wasevaporated off and the crystalline residue was recrystallized frommethanol-ether giving the desired (+)-3-(3-methoxyphenyl)-piperidinehydrochloride (2.54 g, 30% total yield of the maximal theoretical) m.p.175.5°-177° C.; [α]²² D+10.1° (C 2.1, CH₃ OH).

Example I11. (+)-3-(3-Methoxyphenyl)piperidine hydrochloride (Method j).

R-(-)-α-Methoxyphenylacetic acid (11.0 g, 0.066 mol) and SOCl₂ (85 ml)was mixed under ice-cooling and the mixture was stirred at 20° for 2 h.Excess of SOCl₂ was evaporated off (at 20° ) and the residual acidchloride oil was dissolved in CH₂ Cl₂. The solution was added at 20° toa stirred mixture of 3-(3-methoxyphenyl)piperidine hydrochloride (15.1g, 0.066 mol), CH₂ Cl₂ (280 ml) and 2.5% aqueous NaOH (560 ml). After 10minutes stirring the phases were separated and the organic phase waswashed once with water and dried (Na₂ SO₄). Filtration and evaporationof the solvent gave 1-(R-α-methoxyphenylacetyl)-3-(3-methoxyphenyl)piperidine as a crude oil (21.8 g).

The crude oil of1-(R-α-methoxyphenylacetyl)-3-(3-methoxyphenyl)-piperidine (21.8 g) waschromatographed on a SiO₂ column (600 g SiO₂) with light petroleum-ether(starting with 50:50 mixture and successively increasing the ethercontent to 100%) as eluant. The fractions containing that one of the twodiastereomers, which is eluated first, in nearly pure form were combinedand the solvent evaporated off giving the desired diastereomeric amideas an oil (7.7 g, 0.023 mmol) (containing 0.5% of the other diastereomeraccording to HPLC). This was dissolved in dry tetrahydrofuran (400 ml)and potassium-tert-butoxide (16.1 g, 0.144 mol) and water (1.33 g, 0.074mol) was added under stirring at room temperature. The mixture wasstirred at this temperature over night and then the mixture waspartitioned between ether and water. After drying (Na₂ SO₄) of theorganic phase excess of HCl-saturated ethanol was added and the solventwas evaporated off. The residue was redissolved twice in absoluteethanol and the solvent evaporated, giving a crystalline residue.Recrystallization from ethanol-ether gave the desired(+)-3-(3-methoxyphenyl)piperidine hydrochloride (4,0 g, 53% total yieldof the maximal theoretical), m.p. 175.5°-177° C.; [α]²² D=+10.1° (C 2.1,CH₃ OH).

Example I12. (-)-3-(3-Methoxyphenyl)-N-n-propylpiperidine hydrochloride(Method j, and n)

(+)-3-(3-Methoxyphenyl)piperidine hydrochloride (1.5 g, 0.0066 mol) wastreated with 2 N NaOH (50 ml) and the free amine was extracted withether. After drying (K₂ CO₃ 3), filtering and evaporation the residualfree amine oil (1.2 g) was dissolved in dry ether (50 ml) and thetriethylamine (1.4 ml, 0.0010 mol) was added. Then propionyl chloride(0.87 ml, 0.0010 mol) dissolved in dry ether (5 ml) was slowly added at0° under stirring, and the mixture was stirred at room temperature for30 min. The precipitate was filtered off and the solvent was evaporatedgiving an oily residue. This residue was dissolved in drytetrahydrofuran (50 ml) and added to a suspension of LiAlH₄ (0.75 g,0.0020 mol) in dry tetrahydrofuran (75 ml) under N₂. After refluxing for4 h. the mixture was hydrolysed, the precipitate was filtered off andthe solvent was evaporated. The residue was dissolved in ether andpassed through an alumina column with ether as eluant. Addition of HClsaturated ethanol, evaporation of the solvent and recrystallization gave(-)-3-(methoxyphenyl)-N-n-propyloiperidine hydrochloride (1.48 g. 83%),200,5-202° C.; [α]²² D -6.7 (C 2.1, CH₃ OH).

Example I13. (-)-3-(3-methoxyphenyl)-N-n-propyl piperidine hydrochloride(Method j and m).

NaBH₄ (0.61 g, 0.016 mol) was added portionwise under stirring to asolution of propionic acid (3.6 g, 0.051 mol) in dry benzene (15 ml).The temperature was kept below 15° C. for 2 h and then(+)-3-(3-methoxyohenyl)-piperidine (0.61 g, 0.0032 mol) dissolved in drybenzene (10 ml) was added and the mixture was refluxed for 3 h. Thereaction mixture was allowed to reach room temperature and was thenextracted with 2.5 M NaOH (20 ml). The aqueous phase was extracted withbenzene, all the benzene phases mixed, dried (Na₂ SO₄) and the solventevaporated giving an oily residue. The product was precipitated ashydrochloride and recrystallized from methanol/ether, yielding the pureproduct (0.60 g, 73%), mp. 200°-202° C.

Preparation of end compounds Example E1.N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (Method a)

N-Propyl-3-(3-methoxyphenyl)piperidine hydrochloride (7.0 g, 0.026 mol)was suspended in 48% HBr (200 ml). The mixture was refluxed undernitrogen for 3 h. The hydrobromic acid was evaporated and the residuewas recrystallized from ethanol/ether, yielding the pure product (6.7 g,86%) mp. 146°-7.5° C.

Example E2. N-pentyl-3-(3-hydroxyphenyl)piperidine hydrochloride (Methoda)

N-pentyl-3-(3-methoxyphenyl)piperidine (1.3 g, 0.005 mol) in CH₂ Cl₂ (20ml) was cooled with dry ice and BBr₃ (1.6 g, 0.006 mol) was addeddropwise. The mixture was then held at -78° C. for 1 h and then allowedto reach r.t. overnight. The solution was made alkaline with aqueous Na₂CO₃, extracted with CH₂ Cl₂ and the organic phase dried with Na₂ SO₄.Evaporation of the solvent afforded an oily residue which was treatedwith HCl-saturated ethanol (5 ml). After evaporation of solvent,purification by extractions and recrystallization (ethanol/ether), thedesired product (0.40 g, 29%) was obtained, mp. 70°-80° C.

Example E3. N-n-Propyl-3-(3-acetoxyphenyl)piperidine hydrochloride(Method c)

N-n-propyl-3-(3-hydroxyphenyl)piperidine (0.8 g, 0.0037 mol) wasdissolved in acetic anhydride (20 ml). Triethylamine (1 ml) was addedand the solution was refluxed for 1.5 h, ethanol (50 ml) was added andthe volatiles were evaporated giving a residual oil. The residue waspartitioned between ether and water. Separation of the two phases andevaporation of the ether gave an oily residue (700 mg). This wasdissolved in dry ether (100 ml) and HCl-saturated ether was added givingthe desired compound as a crystalline precipitate, which was filteredoff and recrystallized from methanol/isopropyl ether. Yield 0.60 g(55%), mp. 173°-175° C.

Example E4. N-n-Propyl-3-(3-benzoyloxyphenyl)piperidine hydrochloride(Method c).

N-n-Propyl-3-(3-hydroxyphenyl)piperidine (0.5 g, 0.0023 mol) wasdissolved in CH₂ Cl₂. Triethylamine (1 ml) and benzoyl chloride (0.5 ml,0.004 mol) was added and the mixture was stirred at r.t. for 48 h. Thesolvent was evaporated and the residue was partitioned between ether andwater. The ether phase was dried (Na₂ SO₄) and the solvent evaporatedgiving an oily residue which was eluated through a short silica gelcolumn with methanol as eluant. Evaporation of the solvent gave an oilyresidue (300 mg). The oil was dissolved in ether and HCl-saturated etherwas added. Filtration and drying gave the desired compound in acrystalline form. Yield 13%, mp. 170° C.

Example E5. 2-[3-(3-Hydroxyphenyl)-piperidino]ethanol hydrochloride(Method d)

Ethylenoxide (0.36 ml, 7.0 mmol) was added to a stirred solution of3-(3-hydroxyphenyl)piperidine (1.0 g, 5.6 mmol) in methanol (150 ml),maintaining the temperature at -30° C., whereafter the reaction mixturewas allowed to reach room temperature. (The reaction was followed byTLC). More ethylenoxide (0.5 ml, 9.8 mmol) was added in portions untilthe reaction was complete (two weeks). An excess of ethereal hydrogenchloride was added and the solvent was evaporated. The oily residue waspassed through a silica column with 10% methanol in chloroform. Afterevaporation the hydrochloride was recrystallized from ethanol/ether toyield 0.6 g (41%) of 2-[3-(3-hydroxyphenyl)-piperidino]ethanolhydrochloride, m.p. 116.5°-120° C.

Example E6. N-n-Propyl-3-(3-hydroxyohenyl)piperidine hydrochloride(Method b)

To a solution of N-n-Propyl-3-(3-aminophenyl)piperidine (0.74 g, 0.0034mol) in 6M H² SO₄ (2 ml) NaNO₂ (0.23 g, 0.0034 mol) dissolved in water(0.6 ml) was added dropwise at 5° C. and then the mixture was stirred at5° C. for 1 h. The resulting mixture was added dropwise to refluxing 10%H₂ SO₄ (3.5 ml) and the reflux was continued for 5 min. Coolingalkalising (Na₂ CO₃), extraction with ether, drying and evaporation ofthe organic phase gave the desired product as a free base. Conversion tothe hydrochloride followed by recrystallization gave 0.22 g (25%) ofN-n-propyl-3-(3-hydroxyphenyl)piperidine hydrochloride, mp. 143.5°-146°C.

Example E7. N-n-Propyl-3-(3-allyloxyphenyl)piperidine hydrochloride(Method e)

A solution of N-n-propionyl-3-(3-allyloxyphenyl)piperidine (0.35 g,0.0013 mol) in dried ether (25 ml) was dropped to a suspension of LiAlH₄(0.35 g) in dried ether under nitrogen and stirring, and the mixture wasrefluxed for 30 min. H₂ O (0.35 ml), 15% NaOH (0.35 ml) and H₂ O (1 ml)were added and the precipitated crystals were filtered off and washedwith ether. The solution was dried with Na₂ SO₉. Evaporation to drynessgave an oily residue which was dissolved in ether. Addition ofHCl-saturated ether resulted in precipitation of white crystals. Thecrystals were centrifugated and treated with light petroleum,centrifugated and dried. Yield 0.185 g (49%).

Example E8. N-n-Propyl-3-(3-benzyloxyphenyl)piperidine hydrochloride(Method c)

A mixture of N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (1.0g. 0.0033 mol), potassium t-butoxide (1.0 g, 0.009 mol) andbenzylchloride (1.0 g, 0.009 mol) in t-butanol (25 ml) was refluxed for1 h. Water was added and the mixture extracted with ether. The organicphase was dried with Na₂ SO₄ and evaporated to dryness giving a paleyellow oily residue. The residue was chromatographed through a silicagel column with methanol as eluant. The pertinent fractions werecollected and evaporated to dryness. The oily residue was dissolved inether and HCl-saturated ether was added, giving white crystals.Evaporation and treatment of the residue with acetone gave 0.60 g (52%)of the desired product as white crystals, mp. 171° C.

Example E9. N-n-Propyl-3[3-(phenylcarbamoyloxy)phenyl]-piperidinehydrochloride (Method c)

A mixture of N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (0.76g, 0.0025 mol), phenylisocyanate (5.45 g, 0.046 mol), triethylamine (0.5g, 0.049 mol) and methylene chloride (2 ml) was stirred at r.t. for 18h. The mixture was partitioned between water and ether. The ether phasewas dried and evaporated giving a partly crystalline residue. Theresidue was dissolved in methanol and chromatographed on a silica gelcolumn (200 g, SiO₂) with methanol as eluant. The fractions whichaccording to GLC contained the desired product in pure form werecontinued and the solvent evaporated. The residue was dissolved in etherand treated with HCl-saturated ether giving a crystalline precipitate.Filtration and washing gave 0.18 g (20%) of the desired hydrochloride,mp. 184°-190° C.

Example E10. N-n-Propyl-3-[2,6-dimethylbenzoyloxy)-phenyl]piperidinehydrochloride (Method c)

A mixture of N-n-Propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (1.0g, 0.00033 mol) 2,6,-dimethylbenzoyl chloride (2.15 g, 0.0127 mol) anddistilled dry pyridine (7 ml) was stirred at room temperature under N-atmosphere for 24 h. Aqueous NaHCO₃ was added and the mixture wasextracted with ether. The organic phase was dried and all the solventswere evaporated giving an oily residue. The residue was eluted throughan alumina column with ether and then through a silica gel column withlight petroleum-ether (1:1) as eluant. The product was then precipitatedby addition of HCl-saturated ether. Filtering and drying yielded 1.2 g(93%) of the pure desired hydrochloride, mp. 190°-191° C.

According to the methods of the Examples above, the following compoundswere prepared and recrystallized as acid addition salts fromethanol/ether or isolated as the bases.

Example E11. (-)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine hydrochloride(Method j).

(-)-(3-Methoxyphenyl)-N-n-propylpiperidine hydrochloride (1.20 g, 0.0044mol) in 48% aqueous HBr was heated at 120° for 4 h under N₂. Thevolatiles were removed in vacuo and the residue was recrystallized frommethanol-ether giving (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidinehydrobromide (1.10 g) mp. 166°-167° C.; [α]²² D -5.8(C 2.0, CH₃ OH). Thehydrobromide was alkalinized with saturated NaHCO₃₃ (25 ml) and themixture was extracted with ether (4×20 ml). The combined ether layerswere dried (Na₂ SO₄), filtered and HCl-saturated ether was added givinga precipitate which was recrystallized giving(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine hydrochloride (0.84 g,75%), mp. 187°-188° C.; [α]²² D -7.1 (C 2.2, CH₃ OH).

Example E12. (-)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine hydrochloride(Method j).

(-)-3-(3-Methoxyphenyl)-N-n-propylpiperidine (1.50 g, 0.0064 mol) wasdissolved in CH₂ Cl₂ (25 ml) and cooled to -78° . BBr₃ (3.0 ml, 0.031mol) was added under stirring. The cooling medium was removed and themixture was allowed to reach room temperature. Alkalinization withexcess 10% Na₂ CO₃, extraction with CH₂ Cl₂, drying (Na₂ SO₄) andevaporation of the solvent gave a yellow oil (1.5 g). The oil wasdissolved in abs. ethanol and excess of HCl-saturated ethanol was added.Evaporation to dryness followed by recrystallization from ether-ethanolgave (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine hydrochloride (1.05 g,64%), mp. 187°-188° C.

Example E13. (-)N-n-Propyl-3-[3-(4-pivaloyloxybenzoyloxy)-phenyl]piperidine hydrochloride (Method 1).

(-)N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrochloride (0.400 g, 1.56mmol) was suspended in dry dichloromethane (4 ml).Pivaloyloxybenzoylchloride (0.413 g, 1.72 mmol) was dissolved in amixture of dichloromethane (4 ml) and pyridine (0.136 g, 1.72 mmol). Thesolution was added to the suspension and the mixture was refluxed for 20hours. The clear solution was cooled, washed with aqueous NaHCO₃ anddried with Na₂ SO₄. After evaporation the residual oil was dissolved inethanol, one equivalent HCl-saturated ethanol was added and the productprecipitated by adding ether. Filtering and drying yielded 360 mg (50%)of the pure desired hydrochloride. Mp. 228°-229° C. [α]²⁰ D (C=1.5,MeOH) (-)9.05° .

Example E14. (-)N-n-Propyl-3-(3-allyloxyphenyl)piperidine hydrochloride(method 1)

(-)N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrochloride (0.255 g, 1mmol) and tetrabutylammonium hydrogen sulphate (0.340 g, 1 mmol) weresuspended in dichloromethane (2 ml) and allylbromide (0.133 g, 1.1mmol). 2-M NaOH (2 ml) was added during two minutes and the mixture wasstirred at room temperature for half an hour. The layers were separatedand the organic layer was dried over Na₂ SO₄. After removal of thesolvent by distillation, the residual oil was dissolved in ether (50ml). A theoretical quantity of tetrabutylammonium iodide wasprecipitated. The precipitate was filtered off and to the filtrate wasadded one equivalent HCl-saturated ether. White crystals of the desiredcompound was obtained. The crystals were filtered, washed on the filterswith ether and dried. Yield 190 mg (65%). Mp. 136°-138° C. [α]²⁰ D(C=1.5 MeOH) (-)7.6° .

Example E15. (-)-N-n-Propyl-3-(3-hydroxyphenyl)piperidine hydrochloride(Method k).

To a solution of the appropriate enantiomeric form ofN-n-propyl-3-(3-aminophenyl)piperidine (0.27 g, 0.0013 mol) in 6M H₂ SO₄(1 ml) NaNO₂ (0.077 g, 0.0011 mol) dissolved in water (0.2 ml) was addeddropwise at 5° C. and then the mixture was stirred at 5° C. for 1 h. Theresulting mixture was added dropwise to refluxing 10% H₂ SO₄ (1.5 ml)and the reflux was continued for 5 min. Cooling, alkalising (Na₂ CO₃),extraction with ether, drying and evaporation of the organic phase gavethe desired product as a free base. Conversion to the hydrochloridefollowed by recrystallization gave 0.059 g (20%) of(-)-N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrochloride, m.p.176°-177° C.

Example E16. (-)-N-n-Propyl-3-(3-allyloxyphenyl)piperidine hydrochloride(Method n).

A solution of the appropriate enantiomeric form ofN-n-propionyl-3-(3-allyloxyphenyl)piperidine (0.04 g, 0.16 mmol) indried ether (5 ml) was dropped to a suspension of LiAlH₄ (0.04 g) indried ether under nitrogen and stirring, and the mixture was refluxedfor 30 min. H₂ O (0.04 ml), 15% NaOH (0.04 ml) and H₂ O (0.2 ml) wereadded and the precipitated crystals were filtered off and washed withether. The solution was dried with Na₂ SO₄. Evaporation to dryness gavean oily residue which was dissolved in ether. Addition of HCl-saturatedether resulted in precipitation of white crystals. The crystals werecentrifuqated and treated with light petroleum, centrifugated and dried.Yield 0.02 g of the end compound having physical properties inaccordance with Example E14.

Example E17. (-)-(3-Decanoyloxyphenyl)-1-propylpiperidine hydrochloride

(-)-3-(3-hydroxyphenyl)-1-propylpiperidine hydrochloride (1.5 g, 5.86mmol) was suspended in dry dichloromethane (15 ml). Decanoylchloride(1.2 g, 6.29 mmol) was dissolved in a mixture of dichloromethane (15 ml)and pyridine (0.5 g, 6.32 mmol). The solution was added to thesuspension and the mixture was refluxed for 20 hours. The clear solutionwas cooled, washed with aqueous NaHCO₃ and dried with Na₂ SO₄. Afterevaporation the residual oil was dissolved in ether and precipitated ashydrochloride salt with one equivalent HCl in ether. The salt wasrecrystallized twice from acetone. Yield: 0.7 g (30%). M.p. 142°-144° C.[α]²⁰ D (C-1.8, MeOH)=-5.6° , MS (70 eV): m/z 373 (5%), 344 (100%), 190(7%).

Example E18.

A mixture of (-)N-propyl-3-(hydroxyphenyl) piperidine base (3.0 g;0.0137 mol) in toluene (40 ml) and propylisocyanate (2.34 g; 0.0274 mol)was refluxed for 4 hours. The solution was evaporated and the residueswere dissolved in ether. HCl-saturated ether was added giving whitecrystals. Filtration and recrystallisation from acetonitrile gave thedesired compound,(-)N-propyl-3-[3-(propylcarbamoyloxy)-phenyl]piperidine. Yield: 75% m.p.186°-188° C. [α]²⁰ D=(-)7.85° [C=2.1; MeOH].

Example E19.

(-)N-propyl-3-[3-(diisopropylcarbamoyloxy)phenyl]piperidine was preparedin analogy with the method for(-)N-propyl-3-[3-(piperidine-carbamoyloxy)phenyl]piperidine according toExample 3 from the corresponding diisopropylcarbamoylchloride. M.p.193°-195° C. [α]²⁰ D (-)5.59° .

Example E 20.

A solution of piperidinecarbonylchloride (4.03 g; 0.0273 mol) and(-)N-propyl-3-(hydroxyphenyl)piperidine (2.0 g; 0.0091 mol) in pyridine(25 ml) was stirred at 60° C. for 4 hours. The pyridine was evaporatedcarefully. The residue was washed with ether and tetrahydrofuran.Recrystallization from acetonitrile afforded the pure product(-)N-propyl-3(3-piperidinecarbonyloxphenyl)piperidine. Yield: 57% m.p.209°-210° C. [α]²⁰ D=(-)8.3° [C=2.1; MEOH].

Example E 21.

(-)N-propyl-3-[3-(3,4-dimethoxyphenylcarbamoyloxy) phenyl]-piperidinewas prepared in accordance with Example 1. M.p. 183°-184° C., [α]²⁰D=1.28° .

Example E 22.

(-)N-propyl-3-[3-(p-chlorophenylcarbamoyloxy) phenyl]-piperidine wasprepared in accordance with Example 1. M.p. 205°-208° C., [α]²⁰ D -5.20°.

Example E 23.

(-)N-propyl-3-[3-p-isopropylcarbamoyloxy)phenyl]piperidine was preparedin accordance with Example 1. M.p. 184°-185° C., [α]²⁰ D=-6.91° .

Example E 24.

(-)N-propyl-3-[3-(p-tert.butylcarbamoyloxy)phenyl]piperidine wasprepared in accordance with Example 1. M.p. 179°-181° C. [α]²⁰ D=-3.05°.

Example E 25.

(-)N-propyl-3-[3-(2-chloro-6-methylphenylcarbamoyloxy)p-phenyl]piperidine was prepared in accordance with Example 1. [α]²⁰ D-4.43° .

    __________________________________________________________________________     ##STR77##                                                                    Compound/                                 Method  Melting                     Example                                   (Ref. to                                                                              point                                                                                  Yield.sup.(a)      No.    n  Y              R           Salt/Base                                                                          Example No.)                                                                          or other                                                                               %ata               __________________________________________________________________________    Intermediates                                                                 I8     2  OCH.sub.3      H           HCl  A2, h   137-138.5(*)                                                                           93                        2  OCH.sub.3      CH.sub.3    HCl  A2, h (Ex. I6)                                                                        153-154(*)                                                                             68                        2  OCH.sub.3      C.sub.2 H.sub.5                                                                           HCl  A2, h (Ex. I6)                                                                        149-150(*)                                                                             46                 I2     1  OCH.sub.3      n-C.sub.3 H.sub.7                                                                         base A1, e   Bp 85-86/C.1(*)                                                                        83                 I6     2  OCH.sub.3      n-C.sub.3 H.sub.7                                                                         HBr  A2, h   155-156(*)                                                                             70                 I4     2  OCH.sub.3      n-C.sub.3 H.sub.7                                                                         HCl  A1, d   191      72                 I1     2  OCH.sub.3      n-C.sub.4 H.sub.9                                                                         HCl  A1, e   130-131(*)                                                                             88                 I3     2  OCH.sub.3      n-C.sub.5 H.sub.11                                                                        base A1, d   NMR.sup.(b)                                                                            25                        2  OCH.sub.3      CH(CH.sub. 3).sub.2                                                                       base A1, d (Ex. I3)                                                                        NMR.sup.(d)                                                                            43                        2  OCH.sub.3      CH.sub.2 C(CH.sub.3).sub.3                                                                base A1, e (Ex. I1)                                                                        NMR.sup.(e)                                                                            81                        2  OCH.sub.3      CH.sub.2 CHCH.sub.2                                                                       base A1, d (Ex. I3)                                                                        NMR.sup.(f)                                                                            30                        2  OCH.sub.3                                                                                     ##STR78##  2.HCl                                                                              A1, d (Ex. I3)                                                                        165-170                                                                                 64.sup.(o)               1  OCH.sub.3                                                                                     ##STR79##  --   A1 (Ex. I2)                                                                           IR.sup.(g)                                                                             100                       2  OCH.sub.3                                                                                     ##STR80##  --   A1 (Ex. I1)                                                                           IR.sup.(h)                                                                             --                        2  OCH.sub.3                                                                                     ##STR81##  --   A1 (Ex. I1)                                                                           IR.sup.(i)                                                                             --                        2  OCH.sub.3                                                                                     ##STR82##  --   A1 (Ex. I2)                                                                           NMR, IR.sup.(j)                                                                        91                 I9     2  NH.sub.2       n-C.sub.3 H.sub.7                                                                         base B2      NMR.sup.(k)                 End Compounds                                                                 1      2  OH             CH.sub.3    HBr  a (Ex. E1)                                                                            169-170(*)                                                                             70                 2      2  OH             C.sub.2 H.sub.5                                                                           HBr  a (Ex. E1)                                                                            158-159(*)                                                                             60                 3      1  OH             n-C.sub.3 H.sub.7                                                                         HBr  a (Ex. E1)                                                                            128-129(*)                                                                             80                 4/E1   2  OH             n-C.sub.3 H.sub.7                                                                         HBr  a       146-147.5(*)                                                                           86                 5      2  OH             n-C.sub.4 H.sub.9                                                                         HBr  a (Ex. E1)                                                                            123-124(*)                                                                             73                 6/E2   2  OH             n-C.sub.5 H.sub.11                                                                        HCl  a       70-80,NMR.sup.(l)                                                                      28                 7      2  OH             CH(CH.sub.3).sub.2                                                                        HCl  a (Ex. E2)                                                                            144-146  23                 8      2  OH             CH.sub.2 C(CH.sub.3).sub.3                                                                HCl  a (Ex. E2)                                                                            oil, NMR.sup.(n)                                                                       14                 9      2  OH             CH.sub.2 CHCH.sub.2                                                                       HCl  a (Ex. E2)                                                                            148-150   4                 10/E3  2                                                                                 ##STR83##     n-C.sub.3 H.sub.7                                                                         HCl  c       173-175  55                 11     2                                                                                 ##STR84##     n-C.sub.3 H.sub.7                                                                         HCl  c (Ex. E4)                                                                            155      33                 12/E4  2                                                                                 ##STR85##     n-C.sub.3 H.sub.7                                                                         HCl  c       170      13                 13/E5  2  OH             CH.sub.2 CH.sub.2 OH                                                                      HCl  d       116.5-120                                                                              41                 14     2  OH             CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                       2.HBr                                                                              a (Ex. E1)                                                                            219-220  60                 15/E6  2  OH             n-C.sub.3 H.sub.7                                                                         HCl  b       143.5-146                                                                              25                 16/E7  2  OCH.sub.2 CHCH.sub.2                                                                         n-C.sub.3 H.sub.7                                                                         HCl  e       NMR.sup.(p)                                                                            49                 17/E8  2                                                                                 ##STR86##     n-C.sub.3 H.sub.7                                                                         HCl  c       171      52                 18/E9  2                                                                                 ##STR87##     n-C.sub.3 H.sub.7                                                                         HCl  c       184-190  20                 19/E10 2                                                                                 ##STR88##     n-C.sub.3 H.sub.7                                                                         HCl  c       190-191  93                 20     2                                                                                 ##STR89##     n-C.sub.3 H.sub.7                                                                         HCl  c (Ex. E10)                                                                           210-214  29                 21     2                                                                                 ##STR90##     CH(CH.sub.3).sub.2                                                                        HCl  c (Ex. E10)                                                                           198-200  70                 22     2                                                                                 ##STR91##     n-C.sub.4 H.sub.9                                                                         HCl  c (Ex. E10)                                                                           82-85    62                 23     1  OH             CH(CH.sub.3).sub.2                                                                        HBr  a (Ex. E1)                                                                            146-148                     24     2  OH             CH.sub.2 CH.sub.2 CH.sub.2 OH                        25     2  OH             CH.sub.2 CH.sub.2 CH.sub.2 SCH.sub.3                 26     2  OH             CH(CH.sub.2 CH.sub.3).sub.2                          __________________________________________________________________________     Footnotes                                                                     (*)Submitted for elemental analysis (C,H,N); All the analyses were            satisfactory.                                                                 .sup.(a) Calculated on the starting phenylpiperidine or pyridinylbenzene.     .sup.(b) δ(CDCl.sub.3) 0.7-3.2 (20H,m), 3.75 (3H,s), 6.6-7.0 (3H,m)     7.0-7.4 (1H,m).                                                               .sup.(c) δ(CDCl.sub.3) 0.7-3.2 (26H,m), 3.75 (3H,s), 6.6-6.95           (3H,m), 6.95-7.35 (1H,m).                                                     .sup.(d) δ(CDCl.sub.3) 1.0 (6H,d), 1.0-3.1 (10H,m), 3.7 (3H,s),         6.55-6.95 (3H,m), 6.95-7.35 (1H,m).                                           .sup.(e) δ(CDCl.sub.3)1.2 (9H,s), 1.2-3.1 (11H,m), 3.7 (3H,s)           6.6-6.9 (3H,m), 6.9-7.35 (1H,m).                                              .sup.(f) δ(CDCl.sub.3) 1.3-3.3 (11H,m), 3.8 (3H,s), 4.9-5.4 (2H,m),     5.55-6.3 (1H,m), 6.6-7.0 (3H,m), 7.0-7.4 (1H,m).                              .sup.(g) νmax 1680 (CO), 1260 (ArOCH.sub.3)                                .sup.(h) νmax 1640 (CO), 1250 (ArOCH.sub.3)                                .sup.(i) ν max 1638 (CO), 1255 (ArOCH.sub.3)                               .sup.(j) δ(CDCl.sub.3) 1.3 (9H,s), 1.4-3.0 (9H,m), 3.8 (3H,s),          6.65-6.95 (3H,m), 7.1-7.45 (1H,m); νmax 1650 cm.sup.-1.                    .sup.(k) δ(CDCl.sub.3) 0.9 (3H,t), 1.15-3.25 (13H,m), 3.5 (2H,          br.s), 6.4-6.75 (3H,m), 6.95-7.3 (1H,m).                                      .sup.(l) δ(CDCl.sub.3) 0.7-3.5 (20H,m), 6.6-6.9 (3H,m), 6.9-7.35        (1H,m), 9.8(1H,br.s).                                                         .sup.(m) δ(CDCl.sub.3) 0.7-3.4 (26H,m), 6.55-6.9 (3H,m) 6.9-7.3         (1H,m), 9.55 (1H, br.s).                                                      .sup.(n) δ(CD.sub.3 OD) 1.1 (9H,s), 1.7-3.6 (11H,m), 5.1 (1H, br.s)     6.6-6.95 (3H,m), 6.95-7.35 (1H,m).                                            .sup.(o) by using dimethyl2-chloroethylamine hydrochloride as alkylating      agent.                                                                        .sup.(p) δCDCl.sub.3 0.92 (3H,t), 1.2-3.2 (16H,m), 4.45-4.65 (2H,m)     5.15-5.30 (1H,m), 5.30-5.60 (2H,m), 5.80-6.40 (1H,m), 6.55-6.90 (3H,m),       7.00-7.35 (1H,m).                                                        

The following examples illustrate how the compounds of the presentinvention may be included into pharmaceutical preparations.

Example P1. Preparation of soft gelatine capsules

500 g of active substance are mixed with 500 g of corn oil, whereuponthe mixture is filled in soft gelatine capsules, each capsule containing100 mg of the mixture (i.e. 50 mg of active substance).

Example P2. Preparation of tablets

0.5 kg of active substance are mixed with 0.2 kg of silicic acid of thetrade mark Aerosil 0.45 kg of potato starch and 0.5 kg of lactose aremixed therewith and the mixture is moistened with a starch pasteprepared from 50 g of potato starch and distilled water, whereupon themixture is granulated through a sieve. The granulate is dried andsieved, whereupon 20 g of magnesium stearate are mixed into it. Finally,the mixture is pressed into tablets each weighing 172 mg.

Example P3. Preparation of a syrup

100 g of active substance are dissolved in 300 g of 95% ethanol,whereupon 300 g of glycerol, aroma and colouring agents (q.s.) and 1000ml of water are mixed therein. A syrup is obtained.

Example P4. Preparation of an injection solution

Active substance (hydrobromide) (1 g), sodiumchloride (0.8 g) andascorbic acid (0.1 g) are dissolved in sufficient amount of distilledwater to give 100 ml of solution. This solution, which contains 10 mg ofactive substance per ml, is used in filling ampoules, which aresterilized by heating at 120° C. for 20 minutes.

Pharmacological evaluation A. Substituted Phenylazacycloalkanes

Drugs acting on central dopamine (DA) transmission have for long beenknown to be clinically effective in a variety of diseases originating inthe CNS, e.g. parkinsonism and schizophrenia. In the former condition,the nigro-neostriatal hypofunction can be restored by an increase inpostsynaptic DA-receptor stimulation, whereas the latter condition canbe normalized by achieving a decrease in postsynaptic DA-receptorstimulation. So far, this decrease has been mainly accomplished eitherby (a) direct blockade of the postsynaptic DA receptors (considered tobe the mode of action for classical antipsychotic agents like e.g.haloperidol and chlorpromazine) or (b) inhibition of intraneuronalpresynaptic events essential for the maintenance of adequateneurotransmission, e.g. granular uptake and storage (cf. the neurolepticreserpine, which is known to deplete the monoamine stores via itsactions upon granular structures), transport mechanisms and transmittersynthesis.

In recent years a large body of pharmacological, biochemical andelectrophysiological evidence has accumulated, providing considerablesupport in favor of the existence of a specific population of centralautoreculatory DA receptors, so-called autoreceptors, located on thedopaminergic neuron itself (i.e. presynaptically located). Thesereceptors are part of a homeostatic mechanism that modulates nerveimpulse flow and transmitter synthesis and thus the amount of DAreleased from the nerve endings.

The well-known direct DA-receptor agonist apomorphine is able toactivate the DA autoreceptors as well as the postsynaptic DA receptors.At low doses, however, the effects of autoreceptor stimulation appear topredominate, whereas at higher doses the (autoreceptor-mediated)attenuation of DA transmission is outweighed by the enhancement inpostsynaptic receptor stimulation. Thus, the "paradoxical" antipsychoticand antidyskinetic effects demonstrated in man after low doses ofapomorphine are most probably to be attributed to theautoreceptor-stimulatory properties of this DA-receptor agonist. Inaccordance with this, and in view of current knowledge of the drawbackslinked to the use of DA-receptor antagonists in the therapy ofschizophrenia and other psychotic disorders, it has been suggested thatDA-receptor stimulants with a high selectivity for CNS DA autoreceptorswould offer new therapeutic principles of great value in psychiatricmedicine. At the moment no such drug is commonly known. While searchingfor new postsynaptic DA-receptor agonists (anti-Parkinson agents), wesurprisingly discovered a group of substances possessing selectiveDA-autoreceptor agonistic properties. In order to investigate this newpharmacological profile, the following experiments were performed. Forcompound numbers see table of "End Compounds" above.

Pharmacological procedures 1. Antagonism of the reserpine-induced"neuroleptic syndrome" in the rat

Depletion of the monoamine stores with reserpine brings about a"neuroleptic syndrome" characterized by hypomotility, catalepsy, musclerigidity, hunch-backed posture as well as a number of other central andperipheral signs of monoamine depletion. This syndrome can be reversedby the administration of drugs that stimulate postsynaptic DA receptorsdirectly or indirectly, e.g. apomorphine, L-Dopa.

Rats (150-300 g) pretreated with reserpine (10 mg/kg i.p., 6 h before)were given compound 4 subcutaneously at different doses. However, noantagonism of the reserpine-induced syndrome was observed, not even atnearly lethal doses. In a similar manner, compound 7 was tested at 20mg/kg s.c., i.e. a dose about 100 times the ED₅₀ in Table I. Noantagonism of the reserpine-induced syndrome was seen.

2. In-vivo determination of rat brain tyrosine hydroxylation.

The compounds under evaluation were tested biochemically for centralDA-receptor (pre- and/or postsynaptic) stimulating activity. The conceptof this biochemical screening method is that a DA-receptor agonist willstimulate the receptor and through regulatory feedback systems effect adecline in tyrosine hydroxylase activity and thus a subsequent reductionin the synthesis rate for DA in the presynaptic neuron. Dopa formation,as determined after in-vivo inhibition of the aromatic L-amino aciddecarboxylase with NSD 1015 (3-hydroxybenzyl-hydrazine hydrochloride),is taken as an indirect measure of DA synthesis rate.

Rats (150-300 g) pretreated with reserpine were given the compoundsunder evaluation. Gross behavioral observations (changes in motility,stereotypies etc.) were made in order to evaluate possible postsynapticdopamine receptor activity. Subsequent administration of NSD 1015,decapitation, brain dissection (corpora striate and the limbicfore-brain), homogenization, centrifugation, ion-exchange chromatographyand spectrofluorimetric measurements (all as described in detail byWikstrom et al., in J. Med. Chem. 21, 864-867, 1978, and referencescited therein), gave the actual Dopa levels. Several doses (n=4-6) weretested in order to obtain dose-response curves for each compound andbrain area. The dose of a compound producing a half-maximal decrease inthe Dopa level in the rat brain part was then estimated. These values(ED₅₀) are presented in Table I.

From studies on many other compounds having autoreceptor activity aswell as postsynaptic activity we know that at a dose representing theED₅₀ value only autoreceptor activation is likely to occur. To obtainpostsynaptic activation higher doses are necessary. (At the moment nocompound with selective postsynaptic DA-stimulating activity is known.)Therefore, independently of other presented evidence (above or below)concerning receptor selectivity, the ED₅₀ values are considered torepresent doses eliciting selective autoreceptor stimulation.

All the compounds in Table I were biochemically active except for thetwo reference compounds tested, which were completely inactive even at180 mol/kg and 90 mol/kg, respectively. Most of the active compoundshave a potency of approximately the same order (ED₅₀ 0.6-4.4). Thesecompounds are considered to be the most suitable for medical use.Compounds with an ED₅₀ value of about 45 mol/kg as forN-propyl-30(3-hydroxyphenyl)pyrrolidine may be considered to be ofborderline interest.

The absence of significant postsynaptic DA-receptor activation at anydose tested indicates that all the active compounds have selectivity forthe autoreceptors (further investigated only for compound 4).

3. Antagonism ofγ-butyrolactone (GBL)-induced increase in rat brain DAsynthesis rate.

The administration of GBL in anesthetic doses inhibits nerve impulseflow in central DA neurons, thus resulting in a loss of theimpulse-mediated feedback control of tyrosine hydroxylase activity andin a subsequent increase in transmitter synthesis rate (which isdetermined as described under 2 above). Since the GBL inhibitionprecludes neuronal feedback actions, antagonistic effects exerted byDA-receptor agonists upon the GBL-induced increase in synthesis are inall probability to be ascribed to their stimulating the DA autoreceptorspresent in the terminal area of the DA neurons.

Rats (150-300 g), were given compound 4 subcutaneously at several doses(n=7) followed by GBL (750 mg/kg i.p., 5 min. later) and NSD 1015 (100mg/kg i.p., 10 min. later). By a subsequent procedure according to 2above the Dopa levels (representing the DA-synthesis rates) weredetermined. In this model compound 4 dose-dependently antagonized theGBL-induced increase in DA synthesis rate (Logarithmically adjusteddose-response data in Table II). The maximal reversal of the GBL-inducedincrease in DA synthesis rate was approximately 160% in the limbicsystem and 110% in corpus striatum. Furthermore, the antagonism could beblocked by haloperidol, hence confirming that the effects are due toactions on DA autoreceptors (Table III).

4. Effect on spontaneous locomotor activity in the rat.

Untreated animals exposed to a new environment display an initial highmotor activity which then gradually declines over a period of time.Administration of DA-receptor agonists (e.g. apomorphine) in doses wherepreferential autoreceptor stimulation is likely to occur, causes adepression of the spontaneous motility mentioned above, considered to bedue to the DA autoreceptor-mediated impairment of central DAtransmission.

Rats (150-300 g) were injected subcutaneously with several doses ofcompounds 4 and after 5 minutes they were individually placed inmotility boxes ("M/P 40 Fc Electronic Motility Meter". Motron Products,Stockholm) and the motor activity (0-30 min.) was quantified. Compound 4exhibits a clear dose-dependent decrease of the initial high motoractivity, the maximal effect, being a 75% decrease from control values,attained at about 8 mg/kg. No locomotor stimulation was ever seen,regardless of the dose used. Pretreatment with a low dose of haloperidol(0.02 mg/kg i.p., 30 min. before), in order to selectively blockDA-autoreceptor sites, at least partly reversed the sedative effectobtained with a low dose (0.5 mg/kg) of compound 4 (Table IV). Moreover,there seems to be a correlation between the decrease in spontaneouslocomotion and the degree of antagonism of the GBL-induced increase inDA synthesis (cf. 3 above) in the limbic areas of rat brain exerted bycompound 4, the per cent decrease of motor activity being roughly 0.6times the per cent reversal of GBL-induced increase in DA-synthesisrate.

5. Turning behavior in rats with acute unistriatal lesion.

In animals with an acute unilateral KCl-lesion (1μ1 25% KCl lesionedside, 1μ1 20% NaCl control side, administered through previouslyimplanted "guide cannulaes") of the striatum, compensatorycounterbalancing adjustments in the intact contralateral striatum arebrought about and therefore no appreciable asymmetry in body posture ortorsion is observed. Disturbances in the balance produces, depending onthe point of attack, ipsi- or alternatively contralateral turning. Inthis model postsynaptically active DA agonists (e.g. apomorphine, highdosage) elicit ipsilateral turning and rotatory behavior whereas DAantagonists (e.g. haloperidol) cause contralateral turning. Consequentlyit could be expected that agents acting exclusively on DA autoreceptorswould produce contralateral turning in the lesioned animals.

Rats (150-300 g) pretreated as above were given compound 4subcutaneously at several dose levels and then the animals were observedfor at least 4 h. As predicted herein, it was demonstrated that compound4, in each dose tested, made the animals turn to the side contralateralto the lesion (Table V). Moreover, their overall appearance wasindicative of a sedative action exerted by compound 4, thuscorroborating the previous findings (cf. 4 above). It was also shownthat the ipsilateral turning and rotatory response after administrationof postsynaptically effective doses of apomorphine (1.0 mg/kg s.c.) wasnot affected by pretreatment with compound 4 (Table V).

6. Other observations.

Further preliminary investigations on the pharmacological profile ofcompound 4 have indicated that it, in contrast to agents stimulatingpostsynaptic DA receptors, is devoid of emetic activity in dogs (atleast at 1 mg/kg i.m.). As opposed to postsynaptically acting DAagonists, compound 4 (8 mg/kg s.c.) also failed to lower the rat rectaltemperature (0-30 min ). It was in fact lacking any measurabletemperature effects.

7. A comparative study of compound 4 and its 3,4-dihydroxy-analogueknown from DE Offenlequngsschrift No. 2 621 536.

Rats (150-300 g) pretreated with reserpine (10 mg/ kg i.p., 6 h before)were given either phys. saline, compound 4 (100 μmol/kg),N-n-propyl-3-(3,4-dihydroxyphenyl)piperidine (100 μmol/kg) orapomorphine (2 mol/kg) subcutaneously and the locomotor activity(accumulated counts 0-60 min.) was quantified by means of Motron boxes(see under 4 above). The results (Table VI) show that, apart from theirDA-autoreceptor actions (ED₅₀ :s; cf, 2 above),N-n-propyl-3-(3,4dihydroxyphenyl)piperidine as well as apomorphine,exhibit strong central postsynaptic DA-receptor stimulatory effects. Incontrast to the latter agonists, compound 4 appeared to selectively acton the DA autoreceptors and hence failed to elicit a motor response thatdiffered more than slightly from control values.

III. New Enantiomers of substituted phenylazacycloakanes

Among the compounds described in EP-Al-0030526, the compoundN-n-propyl-3-(3-hydroxyphenyl)-piperidine, hereinafter referred to as3-PPP, was presented in greatest detail.

It was shown that 3-PPP and its congeners are capable of inhibiting thephysiological activity of central dopaminergic neurons by activating asubpopulation of dopaminergic receptors presumably located on thedopaminergic neuron itself, i.e. presynaptic receptors or autoreceptors.The effect proved to be selective, in that no concomitant activation ofthe classical postsynaptic dopaminergic receptors could be detected.

These observations were made on racemic mixtures. The two enantiomers of3-PPP have now been tested separately. Surprisingly the levorotatoryenantiomer, (-)-3-PPP, not only was capable of activating thepresynaptic dopaminergic receptors (autoreceptors) but concomitantlyreduced the sensitivity of the postsynaptic dopaminergic receptors todopaminergic agonists. By the combined activation of presynapticreceptors and partial blockade of postsynaptic receptors the inhibitoryaction on dopaminergic neurotransmission will be stronger than by eithereffect alone. In other words, the levorotatory enantiomer is superior tothe racemic mixture as an inhibitor of dopaminergic neurotransmission byacting both presynaptically as an agonist and postsynaptically as anantagonist.

The reason for the difference in pharmacological profile between thelevorotatory enantiomer and the racemic mixture has been clarified: thedextrorotatory enantiomer was found to be a dopaminergic receptoragonist by activating both the presynaptic and the postsynapticreceptors. Thus, the two enantiomers antagonize each other on thepostsynaptic dopaminergic receptor. As a consequence, the racemicmixture will be active only on the presynaptic receptor (autoreceptor).The pharmacological tests demonstrating the properties of the twoenantiomers of 3-PPP are presented below.

1. Evidence for presynaptic dopaminergic receptor (autoreceptor) agonistactivity of both enantiomers of 3-PPP.

Both enantiomers of 3-PPP cause a dose-dependent decrease in spontaneousexploratory motor activity of rats. In male Sprague-Dawley rats injectedsubcutaneously with either enantiomer of 3-PPP and 5 min later placed inMotron boxes for measurement of motor activity the number of countsduring the first 30 min was recorded at doses between 0.053 and 64mg/kg. Both enantiomers cause a decrease of locomotor activity to 30-40%of control. However, the (+)-enantiomer causes a decrease only afterdoses between 0.25 and 4 mg/kg s.c. After 8 mg/kg there is no effect,and after 64 mg/kg there is a significant increase to more than 200% ofcontrol. In contrast, the (-)-enantiomer causes a decrease after allthese doses, with no reversal of the effect after larger doses.

In the dopaminergic neurotransmission L-tyrosine is hydroxylated toL-dopa, which is decarboxylated to the transmitter substance dopamine.After inhibition of the aromatic amino acid decarboxylase by means of3-hydroxybenzylhydrazine HCl (NSD 1015) both enantiomers of 3-PPP causea dose-dependent decrease at doses between 0.053 and 64 mg/kg in theformation of dopa in dopamine-rich brain regions of rats pretreated withreserpine or gammabutyrolactone (GBL). Pretreatment with GBL andprobably also reserpine precludes the influence of postsynaptic dopaminereceptors on dopa formation and thus provides the opportunity to studythe influence of presynaptic autoreceptors separately (cf. Hjorth etal., Life Sci. Vol. 28, pp. 1225-1238, 1981). The effect of bothenantiomers on dopa formation is blocked by the dopamine-receptorantagonist haloperidol. These finds provide strong evidence forstimulation of presynaptic dopamine receptors (autoreceptors).

In rats not pretreated with GBL or reserpine the two enantiomers actdifferently on dopa formation at doses between 0.053 and 64 mg/kg: the(+)-form causes a decrease, whereas the (-)-form causes an increase indopa formation in the striatum and no change in the limbic region. Thesechanges in dopa formation are matched by corresponding changes in thelevels of the dopamine metabolites 3,4-dihydroxyphenyl acetic acid andhomovanillic acid. This differential action of the two enantiomers willbe commented on below.

2. Evidence for postsynaptic dopaminergic receptor agonist activity of(+)-3-PPP.

In reserpine-treated rats (+)-3-PPP causes a marked stimulation oflocomotor activity at doses between 0.25 and 64 mg/kg. The effect isblocked by haloperidol. These findings provide strong evidence for astimulating action of (-)-form causes only a very weak stimulation ofmotor activity in reserpine-pretreated rats, indicating virtual absenceof stimulating action on postsynaptic dopaminergic receptors.

3. Evidence for postsynaptic dopminergic receptor antagonist activity of(-)-3-PPP.

The locomotor stimulating action of the dopamine receptor aqonistapomorphine is antagonized by (-)-3-PPP. This effect is clearcut after adose of 8 mg/kg s.c. of (-) -3-PPP, but not after 2 mg/kg. Thus thepostsynaptic receptor antagonist activity requires a larger dose thanthe presynaptic receptor agonist activity, which is evident after dosesdown to 0.25 mg/kg. The above-mentioned ability of (-)-3-PPP tostimulate dopa formation and to raise dopaminemetabolite levels in ratstriatum provides further evidence for blockade of postsynaptic dopaminereceptors, resulting in feedback-mediated stimulation of dopaminergicneurons.

Further, (-)-3-PPP and racemic 3-PPP have been compared regardingantagonism of apomorphine-induced locomotor stimulation. Either form of3-PPP was injected subcutaneously in a dose of 8 mg/kg 20 min andapomorphine in a dose of 1 mg/kg subcutaneously 5 min before placing therats in the Motron for 30 min. Shown are the counts per 30 min., means±s.e.m. and number of experiments (n). As demonstrated in Table 1(-)-3-PPP antagonized said stimulation while the racemate did not.

The (-)-form of 3-PPP has a striking antagonistic action against thelocomotor stimulating activity of (+)-amphetamine. This effect isprobably the result of the simultaneous stimulation of presynapticdopaminergic receptors and partial blockade of postsynaptic dopaminergicreceptors. All the major antipsychotic agents in current use are potentamphetamine antagonists, and such activity is considered to bepredictive of antipsychotic action.

The compounds of the invention are believed to exert their main activityafter metabolism to the corresponding compound of formula bII above.Thus the compounds of the invention are believed to be prodrugs orbioprecursors of said compound of formula bII. The compounds of theinvention possess an improved oral absorption as compared with thecompound of formula II and other previously described compounds.

CONCLUSION

The pharmacological data affirm the hypothesis that the compounds underconsideration are centrally acting selective DA autoreceptor stimulatingagents, and thus of great clinical interest in the treatment ofpsychotic disorders such as schizophrenia and a number of other diseasestates such as tardive dyskinesia, Huntington's chorea,hypoprolactinemia, alcoholism and drug abuse, said psychotic disordersand other disease states possibly being associated with a pathologicalincrease in central DA transmission.

Extrapyramidal motor disturbances of choreatic type are avoided with theenantiomer compounds of the invention. As compared with the racemates,the pure enantiomers of the invention have a better efficacy in thesuggested treatment in having an unexpected postsynaptic dopamineantagonist activity in addition to the presynaptic dopamine antagonistactivity.

                                      TABLE I                                     __________________________________________________________________________     ##STR92##                                                                    Compound                         Salt                                                                              ED.sub.50 *                                                                        (μmol/kg s.c.)                   No.   n Y              R'        Base                                                                              Limbic                                                                             Striatum                            __________________________________________________________________________     1    2 OH             CH.sub.3  HBr 2.1  1.5                                  2    2 OH             C.sub.2 H.sub.5                                                                         HBr 4.4  4.2                                  3    1 OH             n-C.sub.3 H.sub.7                                                                       HBr ˜45                                                                          ˜45                            4.sup.(3)                                                                          2 OH             n-C.sub.3 H.sub.7                                                                       HBr 2.7  2.7                                  5    2 OH             n-C.sub.4 H.sub.9                                                                       HBr 1.7  0.7                                  6    2 OH             n-C.sub.5 H.sub.11                                                                      HCl 0.9  0.6                                  7.sup.(3)                                                                          2 OH             CH(CH.sub.3).sub.2                                                                      HCl 0.8  0.7                                  9    2 OH             CH.sub.2 CHCH.sub.2                                                                     HCl 4.2  4.0                                 10    2                                                                                ##STR93##     n-C.sub.3 H.sub.7                                                                       HCl 1.2  1.5                                 11    2                                                                                ##STR94##     n-C.sub.3 H.sub.7                                                                       HCl 2.2  1.7                                 12.sup.(3)                                                                          2                                                                                ##STR95##     n-C.sub.3 H.sub.7                                                                       HCl 1.8  2.0                                 13    2 OH             CH.sub.2 CH.sub.2 OH                                                                    HCl ˜20                                                                          ˜20                           14    2 OH             CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                     2-HBr                                                                             ˜20                                                                          ˜20                           16.sup.(3)                                                                          2 OCH.sub.2 CHCH.sub.2                                                                         n-C.sub.3 H.sub.7                                                                       HCl <45  <45                                 17.sup.(3)                                                                          2                                                                                ##STR96##     n-C.sub.3 H.sub.7                                                                       HCl <45  <45                                 18    2                                                                                ##STR97##     n-C.sub.3 H.sub.7                                                                       HCl <45  <45                                 19.sup.(3)                                                                          2                                                                                ##STR98##     n-C.sub.3 H.sub.7                                                                       HCl <45  <45                                 20.sup.(3)                                                                          2                                                                                ##STR99##     n-C.sub.3 H.sub.7                                                                       HCl <45  <45                                 21.sup.(3)                                                                          2                                                                                ##STR100##    CH(CH.sub.3 ).sub.2                                                                     HCl 0.5  0.5                                 22    2                                                                                ##STR101##    n-C.sub.4 H.sub.9                                                                       HCl <2.7 <2.7                                23    1 OH             CH(CH.sub.3).sub.2                                                                      HBr                                                2 OCH.sub.3      n-C.sub.3 H.sub.7                                                                       HBr I.sup.(1)                                                                          I.sup.(1)                                 1 OH             H         HBr I.sup.(2)                                                                          I.sup.(2)                           __________________________________________________________________________     I = inactive.                                                                 .sup.(1) ED.sub.50 >180 μmol/kg.                                           .sup.(2) ED.sub.50 >90 μmol/kg.                                            *Gross behavioural observations revealed no significant postsynaptic          DAreceptor activation.                                                        .sup.(3) Also tested with oral administration in the rat at 180 μmol/k     without pretreatment with reserpine. All the compounds tested were active     in reducing dopa accumulation.                                           

                  TABLE II                                                        ______________________________________                                                     % Reversal of GBL-induced                                                     increase in dopamine synthesis                                   Compound 4   rate                                                             mg/kg s.c.   Limbic system                                                                             Corpus strietum                                      ______________________________________                                        0.5           58          0                                                   1.0           75         17                                                   2.0           92         34                                                   4.0          109         51                                                   8.0          126         68                                                   16.0         142         86                                                   ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Blockade of compound 4-induced reversal of                                    the GBL-elicited increase in DA synthesis                                     rate.                                                                                   Dopa concentration ng per                                                     g tissue        Number of                                           Treatment   Limbic system                                                                             Striatum  animals                                     ______________________________________                                        Control (NaCl)                                                                            307 ± 13  660 ± 40                                                                            18                                          Control (GBL)                                                                             506 ± 24 2366 ± 103                                                                           18                                          Compound 4(32 mg/                                                                         191 ± 16.sup.1                                                                         1063 ± 74.sup.1                                                                       5                                          /kg s.c.)- GBL                                                                Haloperidol(1 mg/                                                                         387 ± 32.sup.2                                                                         2193 ± 53.sup.2                                                                       3                                          /kg i.p.)-(32 mg/kg                                                           compound 4)                                                                   ______________________________________                                         .sup.1 Significant, p < 0.001 versus GBLcontrol values (B).                   .sup.2 Not significant, p < 0.05 versus GBLcontrol values (B).           

                  TABLE IV                                                        ______________________________________                                        Antagonism of the compound 4-induced depression                               of locomotor activity in rats.                                                                  Motor activity                                                                (acc. counts                                                                              Number of                                       Treatment         0-15 min)   animals                                         ______________________________________                                        Glucose (i.p., 25 min                                                                           117 ± 17 6                                               before measurement) +                                                         physiological saline                                                          (s.c. 5 min before                                                            measurement)                                                                  Haloperidol (0.02 mg/kg                                                                         140 ± 22 5                                               i.p., 25 min before                                                           measurement) + physio-                                                        logical saline (s.c., 5                                                       min before measurement)                                                       Glucose (i.p., 25 min                                                                           43 ± 9   5                                               before measurement) +                                                         compound 4 (0.5 mg/kg s.c.,                                                   5 min before measurement)                                                     Haloperidol (0.02 mg/kg                                                                          80 ± 10.sup.1                                                                         7                                               i.p., 25 min before                                                           measurement) - compound 4                                                     (0.5 mg/kg s.c., 5 min                                                        before measurement)                                                           ______________________________________                                         .sup.1 Significantly different from group C, p < 0.025.                  

                                      TABLE V                                     __________________________________________________________________________    Turning behaviour in rats with acute unistriatal KCl lesion.                  Compound 4                                                                                 Turning                                                          Dose   Number of                                                                           Ipsi                                                                              Contra    Duration                                                                            Apomorphine-.sup.c                           (mg/kg s.c.)                                                                         animals                                                                             lateral                                                                           lateral                                                                           Catalepsy.sup.a                                                                     of turning                                                                          induced turning                              __________________________________________________________________________    32     8     0   8   +     >4 h  Ipsi 8/8                                     8      4     0   4   -     >4 h  Ipsi 4/4                                     4      2     0   2   -     NT.sup.b                                                                            NT                                           2      4     0   4   -     >2 h  Ipsi 4/4                                     1      2     0   2   -     NT.sup.                                                                             NT                                           __________________________________________________________________________     .sup.a + present, - absent                                                    .sup.b NT = not tested                                                        .sup.c apormorphine 1.0 mg/kg s.c. injected 1 h after compound 4.        

                                      TABLE VI                                    __________________________________________________________________________    Comparison of compound 4 with two known dopaminergic agonists.                                  Motor activity                                                                         Number                                                                             ED.sub.50 (μmol/kg s.c.)                                     (acc. counts                                                                           of   (cr. table 1)                                 Treatment         0-60 min postinj.)                                                                     animals                                                                            Limbic                                                                             Striatum                                 __________________________________________________________________________    Control (0.9% saline)                                                                           15 ± 5                                                                              4    --   --                                       Compound 4 (100 μmol/kg s.c.)                                                                55 ± 4                                                                              3    2.7  2.7                                      N-n-propyl-3-(3',4'-dihydroxy-                                                                  522 ± 83                                                                            3    9.4  10.0                                     phenyl)-piperidine (100 μmol/kg s.c.)                                      Apomorphine (2 μmol/kg s.c.)                                                                 624 ± 51                                                                            4    0.19 0.22                                     __________________________________________________________________________    Antagonism of apomorphine-induced locomotor stimulation.                      Vehicle (control)  174 ± 15    (10)                                        Apomorphine        513 ± 35    (10).sup.a                                  (-)-3-PPP + Apomorphine                                                                          276 ± 50    (5).sup.b                                   (±)-3-PPP + Apormorphine                                                                      443 ± 26    (5).sup.c                                   __________________________________________________________________________     .sup.a differs from control, p<0.001                                          .sup.b differs from apomorphine, p<0.005                                      .sup.c not significantly different from apomorphine.                     

Best Mode of Carrying Out the Invention

The compound N-n-propyl-3-(3-hydroxphenyl)piperidine and its pureenantiomer (-)-N-n-propyl-3-3(3-hydrophenyl) piperidine and its salts,processes for preparing said compound and methods of employing saidcompound in therapy represent the best mode of carrying out theinvention known at present. Other compounds of great value areN-butyl-3-(3-hydroxphenyl)piperidine,N-pentyl-3-(3-hydroxphenyl)piperidine, andN-isopropyl-3-(3-hydroxphenyl)piperidine.

We claim:
 1. A process for the preparation of a compound of the formula ##STR102## wherein n is 2, Y is OH, R¹ COO, R² R³ NCOO-- or R⁴ O and wherein R¹ is an alkyl group having 1-5 carbon atoms or a substituted phenyl group, R² is an alkyl group having 1-5 carbon atoms, a phenethyl, benzyl or phenyl group, R³ is H or an alkyl group having 1-5 carbon atoms and R⁴ is an allyl or benzyl group, an dR is an alkyl group having 1-5 carbon atoms, an hydroxyalkyl, dimethylaminoalkyl or methylthioalkyl group having 2-6 carbon atoms in the alkyl part and having the heteroatom bound in a position other than the 1 position, an alkenyl group having 3-5 carbon atoms other than a 1-alkenyl group, as the base or pharmaceutically acceptable acid addition salt thereof, comprising the steps of(a) hydrogenating a compound of the formula ##STR103## to form a first intermediate compound of the formula ##STR104## wherein R^(a) is an alkyl group of from 1-5 carbon atoms or an acyl group of from 2-6 carbon atoms; (b) reacting the first intermediate compound with an alkylating group selected from the group consisting of alkyl halides, hydroxyalkyl halides, dimethylaminoalkyl halides, methylthioalkyl halides, alkenyl halides, benzyl halides, alkyl tosylates, hydroxyalkyl tosylates, dimethylaminolakyl tosylates, methylthioalkyl tosylates, alkenyl tosylates, benzyl tosylates, carboxylic acid-sodium borohydride complexes of the formula R^(b) COOH-NaBH₄, wherein R^(b) CH₂ -- equals R¹, 2epoxy alkanes and a mixture of formaldehyde and Na(CN)BH₃ to form a second intermediate compound of the formula ##STR105## and (c) cleaving the ether or ester bond of the second intermediate compound to form a compound of formula I wherein Y is a hydroxy group.
 2. A method according to claim 1, further comprising the step of reacting the hydroxy compound of step (c), with a carboxylic acid halide R¹ COX or anhydride (R¹ CO)₂ O to form a compound of formula I wherein Y is R¹ COO--.
 3. A method according to claim 1, further comprising the steps of reacting the hydroxy compound of step (c) with a carbamoyl halide R² R³ NCOX or isocyanate R² NCO in the presence of a base or acid to form a compound of formula I wherein Y is R² R³ NCOO--.
 4. A method according to claim 1, further comprising the step of reacting the hydroxy compound of step (c) with an allyl or benzyl halide R⁴ X in the presence of a base to form a compound of formula I wherein Y is R⁴ O--.
 5. A method according to claim 1, wherein the compound hydrogenated in step (a) is a single purified optical isomer and the compound produced by step (c) is a single purified optical isomer.
 6. A method according to claim 2, wherein the compound hydrogenated in step (a) is a single purified optical isomer and the compound produced by step (c) is a single purified optical isomer.
 7. A method according to claim 3, wherein the compound hydrogenated in step (a) is a single purified optical isomer and the compound produced by step (c) is a single purified optical isomer.
 8. A method according to claim 4, wherein the compound hydrogenated in step (a) is a single purified optical isomer and the compound produced by step (c) is a single purified optical isomer. 